Pyridone derivatives and process for preparing the same

ABSTRACT

A process for preparing a pyridone derivative ( 4 ), which comprises reacting the compound ( 1 ) with a hypochlorite or a hypobromite or with lead tetraacetate to give the compound ( 2 ), and reacting the compound ( 2 ) with the compound ( 3 ). Said process is preferably especially from the standpoint of safety.  
                 
 
     wherein R 1  is hydrogen, alkyl, substituted alkyl, etc.; Y 1  is hydrogen, alky, substituted alky, etc.; Y 2  and Y 3  are indenpently hydrogen, halogen, etc.; and L is alkyl, substituted alkyl, etc.

TECHNICAL FIELD

[0001] The present invention relates to a pyridone derivative or a saltthereof, which exhibits acyl-CoA: cholesterol acyl transferase (ACAT)inhibitory activity, and is useful as an agent for treatment ofhyperlipidemia and atherosclerosis, and a process for preparing thesame.

PRIOR ART

[0002] Cerebral vessel disorders such as stroke, and myocardialinfarction, which rank in high in causes of death in developedcountries, break out with being accompanied by atherosclerosis as basaldisease. From the results of epidemiology research, it is pointed outthat hypercholesterolemia is one of risk factors for atherosclerosis,and there are mainly used anti-hyperlipidemic agents, which can reducecholesterol level in blood, in the prophylaxis or treatment thereof.However, there is no sufficiently effective agent in terms of theefficacy thereof. Recently, it is observed that cells derived frommacrophage accumulate cholesterol ester droplet within the cells andbecome foam cells in atherosclerotic lesions, and it is clarified thatthese foam cells deeply participate in the developments ofatherosclerotic lesions (Arteriosclerosis, 10, 164-177, 1990). Inaddition, it is reported that ACAT activity is increased and cholesterolesters are accumulated in the vascular wall of atherosclerotic lesions(Biochem. Biophys. Acta, 617, 458-471, 1980). Therefore, an inhibitor ofACAT, which catalyses cholesterol esterification, is expected tosuppress the formation or the development of atherosclerotic lesions asa result of the inhibition of foam cell formation and of cholesterolester accumulation in lesions.

[0003] On the other hand, cholesterol in food is absorbed in the freeform at intestinal epidermal cells, and then released in the form ofchylomicron esterified by ACAT into the blood. Therefore, an inhibitorof ACAT is expected to reduce the cholesterol level in the blood by theinhibition of absorption of cholesterol in food at the intestine and ofreabsorption of cholesterol released into the intestine (J. Lipid.Research, 34, 279-294, 1993).

[0004] JP-A-3-181465, JP-A-3-223254 and JP-A-6-501025 disclose somekinds of quinoline derivatives having an ACAT inhibitory activity, andJP-A-5-32666 discloses some kinds of thienopyridine derivatives havingan ACAT inhibitory activity, and further JP-A-9-48780 discloses somekinds of naphthyridine derivatives having an ACAT inhibitory activity.

[0005] These patent publications disclose processes for preparation ofthese compounds, for example, in the above JP-A-9-48780, anureidonaphthyridine derivative which is a pyridone derivative and itsintermediate, an amino derivative are prepared by the following process.

[0006] wherein Ring A is a substituted or unsubstituted pyridine ring;R¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, acycloalkyl group, or a substituted cycloalkyl group; Y¹ is an alkylgroup, a substituted. alkyl group, a cycloalkyl group, a substitutedcycloalkyl group, an aromatic group, or a substituted aromatic group; Lis an alkyl group, a substituted alkyl group, an alkenyl group, asubstituted alkenyl group, a cycloalkyl group, a substituted cycloalkylgroup, an aromatic group, or a substituted aromatic group.

[0007] That is, a carboxy derivative of the formula (11) is azidatedwith an azidating agent, and subsequently heated to convert into anisocyanate derivative of the formula (12), which is further reacted withan amine derivative of the formula (3) to give an ureido derivative ofthe formula (13), or alternatively the isocyanate derivative (12) ishydrolyzed to give an amine derivative of the formula (14).

DISCLOSURE OF INVENTION

[0008] However, the present inventors have found that the azidatingagents used in the above process and the compounds prepared by azidatingthe carboxyl derivative of the formula (II) have a risk of explosion andtherefore, they are not suitable for large-scale production with respectto safety.

[0009] An object of the present invention is to provide a process forpreparing pyridone derivatives and aminopyridone derivatives, especiallya preferable process thereof with respect to safety, and to provide anovel pyridone derivative.

[0010] The present inventors have intensively studied in order to solvethe above problems, and have found that pyridone derivatives andaminopyridone derivatives can safely be prepared by the followingProcesses [1] to [37], and further have found that novel pyridonederivatives of the following [38] to [54] exhibit a potent ACATinhibitory activity, and then have accomplished the present invention.

[0011] That is, the gist of the present invention is as follows.

[0012] [1] A process for preparing a pyridone derivative of the formula(4):

[0013] wherein R¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, an alkenyl group, a substituted alkenyl group, an alkynylgroup, a substituted alkynyl group, a cycloalkyl group, or a substitutedcycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, a cycloalkyl group, a substituted cycloalkyl group, anaromatic group, or a substituted aromatic group; Y² and Y³ areindependently a hydrogen atom, a halogen atom, a hydroxy group, a cyanogroup, a trifluoromethyl group, a nitro group, an amino group, amono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxygroup, a lower alkyithio group, a lower alkylsulfinyl group, a loweralkylsulfonyl group, an alkyl group, a substituted alkyl group, acycloalkyl group, a substituted cycloalkyl group, an aromatic group, asubstituted aromatic group, or Y² and Y³ may combine each other togetherwith the carbon atoms to which they bond, and form a substituted orunsubstituted pyridine ring; and L is an alkyl group, a substitutedalkyl group, an alkenyl group, a substituted alkenyl group, a cycloalkylgroup, a substituted cycloalkyl group, an aromatic group, or asubstituted aromatic group,

[0014] which comprises reacting a compound of the formula (1):

[0015] wherein R¹, Y¹, Y² and Y³ are as defined above, with ahypochlorite or a hypobromite or with lead tetraacetate to give acompound of the formula (2):

[0016] wherein R¹, Y¹, Y² and Y³ are as defined above, followed byreacting the compound (2) with a compound of the formula (3):

L—NH₂  (3)

[0017] wherein L is as defined above.

[0018] [2] The process according to the above [1], wherein a sodiumhypochlorite or a sodium hypobromite is used in the reaction from thecompound (1) to the compound (2).

[0019] [3] The process according to the above [1], wherein leadtetraacetate is used in the reaction from the compound (1) to thecompound (2).

[0020] [4] The process for preparing the pyridone derivative accordingto any one of the above [1] to [3], wherein Y² and Y³ combine each othertogether with the carbon atoms to which they bond, and form asubstituted or unsubstituted pyridine ring, and said pyridine ring is agroup of the following formula (a), (b) or (c):

[0021] [5] The process for preparing the pyridone derivative accordingto any one of the above [1] to [3], wherein Y² and Y³ combine each othertogether with the carbon atoms to which they bond, and form asubstituted or unsubstituted pyridine ring, and said pyridine ring is agroup of the following formula (a):

[0022] [6] The process for preparing the pyridone derivative accordingto the above [4] or [5], wherein Y¹ and L are a substituted aromaticgroup, and R¹ is a substituted or unsubstituted alkyl group.

[0023] [7] The process for preparing the pyridone derivative accordingto the above [6], wherein Y¹ is a 3-methoxyphenyl group, L is a2,6-diisopropylphenyl group, and R¹ is a butyl group.

[0024] [8] A process for preparing a pyridone derivative of the formula(4):

[0025] wherein R¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, an alkenyl group, a substituted alkenyl group, an alkynylgroup, a substituted alkynyl group, a cycloalkyl group, or a substitutedcycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, a cycloalkyl group, a substituted cycloalkyl group, anaromatic group, or a substituted aromatic group; Y² and Y³ areindependently a hydrogen atom, a halogen atom, a hydroxy group, a cyanogroup, a trifluoromethyl group, a nitro group, an amino group, amono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxygroup, a lower alkylthio group, a lower alkylsulfinyl group, a loweralkylsulfonyl group, an alkyl group, a substituted alkyl group, acycloalkyl group, a substituted cycloalkyl group, an aromatic group, asubstituted aromatic group, or Y² and Y³ may combine each other togetherwith the carbon atoms to which they bond, and form a substituted orunsubstituted pyridine ring; and L is an alkyl group, a substitutedalkyl group, an alkenyl group, a substituted alkenyl group, a cycloalkylgroup, a substituted cycloalkyl group, an aromatic group, or asubstituted aromatic group,

[0026] which comprises reacting a compound of the formula (5):

[0027] wherein R¹, Y¹, Y² and Y³ are as defined above, with a compoundof the formula (6):

XCO₂R²  (6)

[0028] wherein R² is a substituted or unsubstituted lower alkyl group,or a substituted or unsubstituted phenyl group; and X is a chorine atomor a bromine atom, to give a compound of the formula (7):

[0029] wherein R¹, R², Y¹, Y² and Y³ are as defined above, followed byreacting the compound (7) with a compound of the formula (3):

L—NH₂  (3)

[0030] wherein L is as defined above.

[0031] [9] The process for preparing the pyridone derivative accordingto the above [8], wherein Y² and Y³ combine each other together with thecarbon atoms to which they bond, and form a substituted or unsubstitutedpyridine ring, and said pyridine ring is a group of the followingformula (a), (b) or (c):

[0032] [10] The process for preparing the pyridone derivative accordingto the above [8], wherein Y² and Y³ combine each other together with thecarbon atoms to which they bond, and form a substituted or unsubstitutedpyridine ring, and said pyridine ring is a group of the followingformula (a):

[0033] [11] The process for preparing the pyridone derivative accordingto the above [9] or [10], wherein Y¹ and L are a substituted aromaticgroup, and R¹ is a substituted or unsubstituted alkyl group.

[0034] [12] The process for preparing the pyridone derivative accordingto the above [11], wherein Y¹ is a 3-methoxyphenyl group, L is a2,6-diisopropylphenyl group, and R¹ is a butyl group.

[0035] [13] A process for preparing an aminopyridone derivative of theformula (5):

[0036] wherein R¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, an alkenyl group, a substituted alkenyl group, an alkynylgroup, a substituted alkynyl group, a cycloalkyl group, or a substitutedcycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, a cycloalkyl group, a substituted cycloalkyl group, anaromatic group, or a substituted aromatic group; and Y² and Y³ areindependently a hydrogen atom, a halogen atom, a hydroxy group, a cyanogroup, a trifluoromethyl group, a nitro group, an amino group, amono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxygroup, a lower alkylthio group, a lower alkylsulfinyl group, a loweralkylsulfonyl group, an alkyl group, a substituted alkyl group, acycloalkyl group, a substituted cycloalkyl group, an aromatic group, asubstituted aromatic group, or Y² and Y³ may combine each other togetherwith the carbon atoms to which they bond, and form a substituted orunsubstituted pyridine ring, which comprises reacting a compound of theformula (1):

[0037] wherein R¹, Y¹, Y² and Y³ are as defined above, with ahypochlorite or a hypobromite or with lead tetraacetate to give acompound of the formula (2):

[0038] wherein R¹, Y¹, Y² and Y³ are as defined above, followed bysubjecting the compound (2) to hydrolysis.

[0039] [14] The process for preparing the aminopyridone derivativeaccording to the above [13], wherein Y² and Y³ combine each othertogether with the carbon atoms to which they bond, and form asubstituted or unsubstituted pyridine ring, and said pyridine ring is agroup of the following formula (a), (b) or (c):

[0040] [15] The process for preparing the aminopyridone derivativeaccording to the above [13], wherein Y² and Y³ combine each othertogether with the carbon atoms to which they bond, and form asubstituted or unsubstituted pyridine ring, and said pyridine ring is agroup of the following formula (a):

[0041] [16] The process for preparing the aminopyridone derivative(according to the above [14] or [15], wherein Y¹ is a substitutedaromatic group, and R¹ is a substituted or unsubstituted alkyl group.

[0042] [17] The process for preparing the aminopyridone derivativeaccording to the above [16], wherein Y¹ is a 3-methoxyphenyl group, andR¹ is a butyl group.

[0043] [18] A process for preparing an aminopyridone derivative of theformula (5):

[0044] wherein R¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, an alkenyl group, a substituted alkenyl group, an alkynylgroup, a substituted alkynyl group, a cycloalkyl group, or a substitutedcycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, a cycloalkyl group, a substituted cycloalkyl group, anaromatic group, or a substituted aromatic group; and Y² and Y³ areindependently a hydrogen atom, a halogen atom, a hydroxy group, a cyanogroup, a trifluoromethyl group, a nitro group, an amino group, amono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxygroup, a lower alkylthio group, a lower alkylsulfinyl group, a loweralkylsulfonyl group, an alkyl group, a substituted alkyl group, acycloalkyl group, a substituted cycloalkyl group, an aromatic group, asubstituted aromatic group, or Y² and Y³ may combine each other togetherwith the carbon atoms to which they bond, and form a substituted orunsubstituted pyridine ring,

[0045] which comprises heating a compound of the formula (8):

[0046] wherein R¹, Y¹, Y² and Y³ are as defined above, and Ring B is asubstituted or unsubstituted benzene ring, in the presence of a base, togive a compound of the formula (9):

[0047] wherein R¹, Y¹, Y², Y³ and Ring B are as defined above, followedby removing the protecting phthaloyl group thereof.

[0048] [19] The process for preparing the aminopyridone derivativeaccording to the above [18], wherein Y² and Y³ combine each othertogether with the carbon atoms to which they bond, and form asubstituted or unsubstituted pyridine ring, and said pyridine ring is agroup of the following formula (a), (b) or (c):

[0049] [20] The process for preparing the aminopyridone derivativeaccording to the above [18], wherein Y² and Y³ combine each othertogether with the carbon atoms to which they bond, and form asubstituted or unsubstituted pyridine ring, and said pyridine ring is agroup of the following formula (a):

[0050] [21] The process for preparing the aminopyridone derivativeaccording to the above [19] or [20], wherein Y¹ is a substitutedaromatic group, and R¹ is a substituted or unsubstituted alkyl group.

[0051] [22] The process for preparing the aminopyridone derivativeaccording to the above [21], wherein Y¹ is a 3-methoxyphenyl group, andR¹ is a butyl group.

[0052] [23] A process for preparing an arninopyridone derivative of theformula (5):

[0053] wherein R¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, an alkenyl group, a substituted alkenyl group, an alkynylgroup, a substituted alkynyl group, a cycloalkyl group, or a substitutedcycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, a cycloalkyl group, a substituted cycloalkyl group, anaromatic group, or a substituted aromatic group; and Y² and Y³ areindependently a hydrogen atom, a halogen atom, a hydroxy group, a cyanogroup, a trifluoromethyl group, a nitro group, an amino group, amono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxygroup, a lower alkylthio group, a lower alkylsulfinyl group, a loweralkylsulfonyl group, an alkyl group, a substituted alkyl group, acycloalkyl group, a substituted cycloalkyl group, an aromatic group, asubstituted aromatic group, or Y² and Y³ may combine each other togetherwith the carbon atoms to which they bond, and form a substituted orunsubstituted pyridine ring,

[0054] which comprises reacting a compound of the formula (1):

[0055] wherein R¹, Y¹, Y² and Y³ are as defined above, with ahypochlorite or a hypobromite.

[0056] [24] The process for preparing the aminopyridone derivativeaccording to the above [23], wherein Y² and Y³ combine each othertogether with the carbon atoms to which they bond, and form asubstituted or unsubstituted pyridine ring, and said pyridine ring is agroup of the following formula (a), (b) or (c):

[0057] [25] The process for preparing the aminopyridone derivativeaccording to the above [23], wherein Y² and Y³ combine each othertogether with the carbon atoms to which they bond, and form asubstituted or unsubstituted pyridine ring, and said pyridine ring is agroup of the following formula (a):

[0058] [26] The process for preparing the aminopyridone derivativeaccording to the above [24] or [25], wherein Y¹ is a substitutedaromatic group, and R¹ is a substituted or unsubstituted alkyl group.

[0059] [27] The process for preparing the aminopyridone derivativeaccording to the above [26], wherein Y¹ is a 3-methoxyphenyl group, andR¹ is a butyl group.

[0060] [28] A process for preparing a pyridone derivative of the formula(4):

[0061] wherein R¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, an alkenyl group, a substituted alkenyl group, an alkynylgroup, a substituted alkynyl group, a cycloalkyl group, or a substitutedcycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, a cycloalkyl group, a substituted cycloalkyl group, anaromatic group, or a substituted aromatic group; Y² and Y³ areindependently a hydrogen atom, a halogen atom, a hydroxy group, a cyanogroup, a trifluoromethyl group, a nitro group, an amino group, amono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxygroup, a lower alkylthio group, a lower alkylsulfinyl group, a loweralkylsulfonyl group, an alkyl group, a substituted alkyl group, acycloalkyl group, a substituted cycloalkyl group, an aromatic group, asubstituted aromatic group, or Y² and Y³ may combine each other togetherwith the carbon atoms to which they bond, and form a substituted orunsubstituted pyridine ring; and L is an alkyl group, a substitutedalkyl group, an alkenyl group, a substituted alkenyl group, a cycloalkylgroup, a substituted cycloalkyl group, an aromatic group, or asubstituted aromatic group,

[0062] which comprises reacting a compound of the formula (3):

L—NH₂  (3)

[0063] wherein L is as defined above, with a compound of the formula(6):

XCO₂R²  (6)

[0064] wherein R² is a substituted or unsubstituted lower alkyl group,or a substituted or unsubstituted phenyl group; and X is a chlorine atomor a bromine atom, to give a compound of the formula (32)

L—NHCO₂R²  (32)

[0065] wherein R² and L are as defined above, following by reacting thecompound (32) with a compound of the formula (5):

[0066] wherein R¹, Y¹, Y² and Y³ are as defined above.

[0067] [29] The process for preparing the pyridone derivative accordingto the above [28], wherein Y² and Y³ combine each other together withthe carbon atoms to which they bond, and form a substituted orunsubstituted pyridine ring, and said pyridine ring is a group of thefollowing formula (a), (b) or (c):

[0068] [30] The process for preparing the pyridone derivative accordingto the above [28], wherein Y² and Y³ combine each other together withthe carbon atoms to which they bond, and form a substituted orunsubstituted pyridine ring, and said pyridine ring is a group of thefollowing formula (a):

[0069] [31] The process for preparing the pyridone derivative accordingto the above [29] or [30], wherein Y¹ and L are a substituted aromaticgroup, and R¹ is a substituted or unsubstituted alkyl group.

[0070] [32] The process for preparing the pyridone derivative accordingto the above [31], wherein Y¹ is a 3-methoxyphenyl group, L is a2,6-diisopropylphenyl group, and R¹ is a butyl group.

[0071] [33] A process for preparing a pyridone derivative of the formula(4):

[0072] wherein R¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, an alkenyl group, a substituted alkenyl group, an alkynylgroup, a substituted alkynyl group, a cycloalkyl group, or a substitutedcycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substitutedalkyl group, a cycloalkyl group, a substituted cycloalkyl group, anaromatic group, or a substituted aromatic group; Y² and Y³ areindependently a hydrogen atom, a halogen atom, a hydroxy group, a cyanogroup, a trifluoromethyl group, a nitro group, an amino group, amono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxygroup, a lower alkylthio group, a lower alkylsulfinyl group, a loweralkylsulfonyl group, an alkyl group, a substituted alkyl group, acycloalkyl group, a substituted cycloalkyl group, an aromatic group, asubstituted aromatic group, or Y² and Y³ may combine each other togetherwith the carbon atoms to which they bond, and form a substituted orunsubstituted pyridine ring; and L is an alkyl group, a substitutedalkyl group, an alkenyl group, a substituted alkenyl group, a cycloalkylgroup, a substituted cycloalkyl group, an aromatic group, or asubstituted aromatic group,

[0073] which comprises reacting a compound of the formula (5):

[0074] wherein R¹, Y¹, Y² and Y³ are as defined above, with a compoundof the formula (6):

L—NCO  (31)

[0075] wherein L is as defined above.

[0076] [34] The process for preparing the pyridone derivative accordingto the above [33], wherein Y² and Y³ combine each other together withthe carbon atoms to which they bond, and form a substituted orunsubstituted pyridine ring, and said pyridine ring is a group of thefollowing formula (a), (b) or (c):

[0077] [35] A process for preparing the pyridone derivative according tothe above 33], wherein Y² and Y³ combine each other together with thecarbon atoms to which they bond, and form a substituted or unsubstitutedpyridine ring, and said pyridine ring is a group of the followingformula (a):

[0078] [36] The process for preparing the pyridone derivative accordingto the above 34] or [35], wherein Y¹ and L are a substituted aromaticgroup, and R¹ is a substituted or unsubstituted alkyl group.

[0079] [37] The process for preparing the pyridone derivative accordingto the above [36], wherein Y¹ is a 3-methoxyphenyl group, L is a2,6-diisopropylphenyl group, and R¹ is a butyl group.

[0080] [38] A pyridone derivative of the formula (10):

[0081] wherein L is an alkyl group, a substituted alkyl group, analkenyl group, a substituted alkenyl group, a cycloalkyl group, asubstituted cycloalkyl group, an aromatic group, or a substitutedaromatic group;

[0082] Z is a direct bond or —NH—;

[0083] R¹ is a hydrogen atom, an alkyl group, a substituted alkyl group,an alkenyl group, a substituted alkenyl group, an alkynyl group, asubstituted alkynyl group, a cycloalkyl group, or a substitutedcycloalkyl group, provided that when Z is a direct bond, then R¹ is nota hydrogen atom;

[0084] Y¹ is a hydrogen atom, an alkyl group, a substituted alkyl group,a cycloalkyl group, a substituted cycloalkyl group, an aromatic group,or a substituted aromatic group;

[0085] Y²² and Y³² are independently a hydrogen atom, a halogen atom, ahydroxy group, a cyano group, a trifluoromethyl group, a nitro group, anamino group, a mono-lower alkylamino group, a di-lower alkylamino group,a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinylgroup, a lower alkylsulfonyl group, an alkyl group, a substituted alkylgroup, a cycloalkyl group, a substituted cycloalkyl group, an aromaticgroup, or a substituted aromatic group, or a salt thereof.

[0086] [39] The pyridone derivative according to the above [38], or asalt thereof, wherein Z is —NH—.

[0087] [40] The pyridone derivative according to the above [39], or asalt thereof, wherein Y¹ is an alkyl group, a substituted alkyl group, acycloalkyl group, a substituted cycloalkyl group, an aromatic group, ora substituted aromatic group.

[0088] [41] The pyridone derivative according to the above [39] or [40],or a salt thereof, wherein one of Y¹, Y² and Y³ is an aromatic group ora substituted aromatic group.

[0089] [42] The pyridone derivative according to the above [39], [40] or[41], or a salt thereof, wherein L is an aromatic group or a substitutedaromatic group.

[0090] [43] The pyridone derivative according to the above [42], or asalt thereof, wherein one of Y¹, Y² and Y³ is a substituted phenylgroup, and one of the substituents thereof is a group of the formula:—M¹—E—Q (M¹ is a direct bond, an oxygen atom, a sulfur atom or a groupof the formula: —NR³— (R³ is a hydrogen atom or a lower alkyl group), Eis a divalent aliphatic hydrocarbon group having 1 to 15 carbon atomsand optionally containing an unsaturated bond, or a phenylene group, Qis a hydrogen atom, a hydroxy group, a carboxyl group, a loweralkoxy-carbonyl group, a benzyloxycarbonyl group, a halogen atom, acyano group, a benzyloxy group, a lower alkoxy group, a loweralkanoyloxy group, a lower alkylthio group, a lower alkylsulfinyl group,a lower alkylsulfonyl group, a benzenesulfonyloxy group being optionallysubstituted by an alkyl group, a lower alkanoylamino group, a loweralkoxycarbonylamino group, a lower alkylsulfonamido group, a phthalimidogroup, a cycloalkyl group, an aryl group, a substituted aryl group, aheteroaryl group, a substituted heteroaryl group, a group of theformula: —NR⁴R⁵ (R⁴ and R⁵ are independently a hydrogen atom, a loweralkyl group, a di-lower alkylamino-substituted lower alkyl group, alower alkoxy-substituted lower alkyl group, a cycloalkyl group, a loweralkoxycarbonyl group, a heteroarylmethyl group, or an aralkyl group, orR⁴ and R⁵ may combine each other together with the nitrogen atom towhich they bond, and form a saturated cyclic amino group having 4 to 8carbon atoms as ones forming the said ring, and optionally having one—NR²⁰—(R²⁰ is a hydrogen atom, a lower alkyl group, a phenyl group, alower alkoxycarbonyl group, or a benzyl group) or one oxygen atom in thecycle thereof), or a group of the formula: —C(═O)NR⁴R⁵(R⁴ and R⁵ are asdefined above)).

[0091] [44] The pyridone derivative according to the above [43], or asalt thereof, wherein Y¹ is a substituted phenyl group.

[0092] [45] The pyridone derivative according to the above [44], or asalt thereof, wherein M¹ is an oxygen atom.

[0093] [46] The pyridone derivative according to the above [43], [44] or[45], or a salt thereof, wherein Q is a hydrogen atom, a hydroxy group,a carboxyl group, a lower alkoxycarbonyl group, a benzyloxycarbonylgroup, a benzyloxy group, a lower alkoxy group, a lower alkanoyloxygroup, a lower alkanoylamino group, a heteroaryl group, a substitutedheteroaryl group, or a group of the formula: —NR⁴R⁵.

[0094] [47] The pyridone derivative according to the above [46], or asalt thereof, wherein E is an alkylene group having 1 to 4 carbon atoms,and Q is a substituted or unsubstituted pyridyl group, a1,2,4-triazol-1-yl group, or a group of the formula: —NR⁴R⁵.

[0095] [48] The pyridone derivative according to the above [43] or [44],or a salt thereof, wherein M¹ is a direct bond.

[0096] [49] The pyridone derivative according to the above [48], or asalt thereof, wherein Q is a hydrogen atom, a hydroxy group, a carboxylgroup, a lower alkoxycarbonyl group, a benzyloxycarbonyl group, abenzyloxy group, a lower alkoxy group, a lower alkanoyloxy group, alower alkanoylamino group, a heteroaryl group, a substituted heteroarylgroup, or a group of the formula: —NR⁴R⁵.

[0097] [50] The pyridone derivative according to the above [48] or [49],or a salt thereof, wherein —E— is a group of the formula:

[0098] (wherein R⁶ and R⁷ are independently a hydrogen atom, a methylgroup, an ethyl group, or a propyl group, or R⁶ and R⁷ may combine eachother to form a 3- to 7-membered cycloalkane ring, m is an integer of 0to 6, and p is an integer of 0 to 6).

[0099] [51] The pyridone derivative according to the above [50], or asalt thereof, wherein p is 0.

[0100] [52] The pyridone derivative according to the above [51], or asalt thereof, wherein R⁶ and R⁷ are both hydrogen atoms, and m is 0 or1.

[0101] [53] The pyridone derivative according to the above [47] or [52],or a salt thereof, wherein R¹ is an alkyl group, a substituted alkylgroup, or a hydrogen atom.

[0102] [54] The pyridone derivative according to the above [53], or asalt thereof, wherein Y²² and Y³² are both hydrogen atoms.

[0103] [55] A pharmaceutical composition containing a pyridonederivative as set forth in any one of the above [38] to [54], or a saltthereof.

[0104] [56] An acyl-CoA: cholesterol acyl transferase (ACAT) inhibitor,which contains as an active ingredient a pyridone derivative as setforth in any one of the above [38] to [54], or a salt thereof.

[0105] [57] An agent for treatment of hyperlipidemia or atherosclerosis,which contains as an active ingredient a pyridone derivative as setforth in any one of the above [38] to [54], or a salt thereof.

[0106] [58] A method for inhibiting acyl-CoA: cholesterol acyltransferase (ACAT), which comprises a administering an effective amountof a pyridone derivative as set forth in any one of the above [38]to[54], or a salt thereof, to a patient in need thereof.

[0107] [59] A method for treatment of hyperlipidemia or atherosclerosis,which comprises administering an effective amount of a pyridonederivative as set forth in any one of the above [38] to [54], or a saltthereof, to a patient in need thereof.

[0108] [60] Use of a pyridone derivative as set forth in any one of theabove [38] to [54], or a salt thereof, in preparation of apharmaceutical composition for inhibiting acyl-CoA: cholesterol acyltransferase (ACAT).

[0109] [61] Use of a pyridone derivative as set forth in any one of theabove [38] to [54], or a salt thereof, in preparation of an agent fortreatment of hyperlipidemia or atherosclerosis.

[0110] Each group in the present invention is explained below.

[0111] Incidentally, throughout the description, when the presentcompounds have substituents such as hydroxy group, amino group,alkylamino group, carboxyl group, etc., then these groups may optionallybe protected when the present methods are carried out. The protectinggroups for hydroxy group, amino group, alkylamino group, carboxyl group,etc., may be conventional protecting groups which are used in the fieldof the organic chemistry, for example, as described in PROTECTIVE GROUPSIN ORGANIC SYNTHESIS, 2nd ed., John Wiley & Sons, Inc.; New York. Forexample, the protected hydroxy group may be benzyloxy group and2-methoxyethoxymethoxy group, and the protected amino group may bebenzylamino group and acetylamino group, and the protected alkylaminogroup may be N-benzyl-N-alkyl-amino group and N-acetyl-N-alkylaminogroup, and the protected carboxyl group may be tert-butoxycarbonyl groupand methoxy-methoxycarbonyl group.

[0112] Ring B is a substituted or unsubstituted benzene ring, and thesubstituted benzene ring has one or more substituents which are the sameor different.

[0113] The substituent of the benzene ring may be, for example, a loweralkyl group, a halogen atom, a cyano group, a trifluoromethyl group, anitro group, a protected amino group, a protected lower alkylaminogroup, a di-lower alkylamino group, a lower alkoxy group, a loweralkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonylgroup, etc.

[0114] The pyridine ring formed by combining Y² and Y³ together with thecarbon atoms to which they bond is a substituted or unsubstitutedpyridine ring, and the nitrogen atom thereof may be located at anyposition except for the fused positions of the fused ring, and thesubstituted pyridine ring has one or more substituents which are thesame or different.

[0115] Besides, the substituent of the pyridine ring formed by combiningY² and Y³ together with the carbon atoms to which they bond may be, forexample, a lower alkyl group, a halogen atom, a cyano group, atrifluoromethyl group, a nitro group, a protected amino group, aprotected lower alkylamino group, a di-lower aIkylamino group, a loweralkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, alower alkylsulfonyl group, etc.

[0116] The alkyl group or the alkyl moiety of the substituted alkylgroup for Y¹, Y², Y³ and R¹ includes, for example, a straight chain orbranched chain alkyl group having 1 to 15 carbon atoms, such as methyl,ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl,1,1-dimethylethyl, pentyl, 3-pentyl, 3-methylbutyl, hexyl, 3-hexyl,4-methyl-pentyl, 4-heptyl, octyl, 4-octyl, decyl, etc.

[0117] The alkenyl group or the alkenyl moiety of the substitutedalkenyl group for R¹ includes, for example, a straight chain or branchedchain alkenyl group having 2 to 15 carbon atoms, such as vinyl, allyl,2-propenyl, 2-methyl-2-propenyl, 2-butenyl, 3-butenyl,3-methyl-2-butenyl, 4-pentenyl, 3-hexenyl, 3-ethyl-2-pentenyl,4-ethyl-3-hexenyl, etc.

[0118] The alkynyl group or the alkynyl moiety of the substitutedalkynyl group for R¹ includes, for example, a straight chain or branchedchain alkynyl group having 3 to 15 carbon atoms, such as 2-propynyl,3-butynyl, 4-pentynyl, 3-hexynyl, 5-methyl-2-hexynyl, 6-methyl-4-heptynyl, etc.

[0119] The alkyl group or the alkyl moiety of the substituted alkylgroup for L includes, for example, a straight chain or branched chainalkyl group having 1 to 20 carbon atoms, such as methyl, ethyl, propyl,2-propyl, butyl, 2-butyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl,3-pentyl, hexyl, heptyl, octyl, undecyl, dodecyl, hexadecyl,2,2-dimethyl-dodecyl, 2-tetradecyl, n-octadecyl, etc.

[0120] The alkenyl group or the alkenyl moiety of the substitutedalkenyl group for L includes, for example, a straight chain or branchedchain alkenyl group having 3 to 20 carbon atoms and having 1 to 2 doublebonds, such as 2-propenyl, 2-butenyl, 3-methyl-2-butenyl, 3-pentenyl,2-octenyl, 5-nonenyl, 4-undecenyl, 5-heptadecenyl, 3-octadecenyl,9-octadecenyl, 2,2-dimethyl-9-octadecenyl, 9,12-octadecadienyl, etc.

[0121] The cycloalkyl group or the cycloalkyl moiety of the substitutedcycloalkyl group includes, for example, a cycloalkyl group having 3 to 8carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, etc.

[0122] The aromatic group includes, for example, an aryl group and aheteroaryl group.

[0123] The aryl group includes, for example, an aryl group having carbonatoms of not more than 10, such as phenyl group, naphthyl group, etc.

[0124] The heteroaryl group includes, for example, a 5- to 6-memberedheteromonocyclic group having 1 to 2 nitrogen atoms, a 5- to 6-memberedheteromonocyclic group having 1 to 2 nitrogen atoms and one oxygen atomor one sulfur atom, a 5-membered heteromonocyclic group having oneoxygen atom or one sulfur atom, a heterobicyclic group formed by fusinga 6-membered ring and a 5- or 6-membered ring and having 1 to 4 nitrogenatoms, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl,3-oxadiazolyl, 1-imidazolyl, 2-imidazolyl, 2-thiazolyl, 3-isothiazolyl,2-oxazolyl, 3-isoxazolyl, 2-furyl, 3-furyl, 3-pyrrolyl, 2-quinolyl,8-quinolyl, 2-quinazolinyl, 8-purinyl, etc.

[0125] The substituted aromatic group has one or more substituents whichare the same or different, and the substituents are, for example, ahalogen atom, a cyano group, a trifluoromethyl group, a nitro group, ahydroxy group, a methylenedioxy group, a lower alkyl group, a loweralkoxy group, a benzyloxy group, a lower alkanoyloxy group, an aminogroup, a mono-lower alkylamino group, a di-lower alkylamino group, acarbamoyl group, a lower alkylaminocarbonyl group, a di-loweralkylaminocarbonyl group, a carboxyl group, a lower alkoxycarbonylgroup, a lower alkylthio group, a lower alkylsulfinyl group, a loweralkyl-sulfonyl group, a lower alkanoylamino group, a loweralkylsulfonamido group, or a group of the formula: —M¹—E—Q (M¹ is adirect bond, an oxygen atom, a sulfur atom, or a group of the formula:—NR³— (R³ is a hydrogen atom or a lower alkyl group), E is a divalentaliphatic hydrocarbon group having 1 to 15 carbon atoms and optionallycontaining an unsaturated bond, or a phenylene group, Q is a hydrogenatom, a hydroxy group, a carboxyl group, a lower alkoxycarbonyl group, abenzyloxycarbonyl group, a halogen atom, a cyano group, a benzyloxygroup, a lower alkoxy group, a lower alkanoyloxy group, a loweralkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonylgroup, a benzenesulfonyloxy group being optionally substituted by analkyl group, a lower alkanoylamino group, a lower alkoxycarbonylaminogroup, a lower alkylsulfonamido group, a phthalimido group, a cycloalkylgroup, an aryl group, a substituted aryl group, a heteroaryl group, asubstituted heteroaryl group, a group of the formula: —NR⁴R⁵ (R⁴ and R⁵are independently a hydrogen atom, a lower alkyl group, a di-loweralkylamino-substituted lower alkyl group, a lower alkoxy-substitutedlower alkyl group, a cycloalkyl group, a lower alkoxycarbonyl group, aheteroarylmethyl group, or an aralkyl group, or R⁴ and R⁵ may combineeach other together with the nitrogen atom to which they bond, and forma saturated cyclic amino group having 4 to 8 carbon atoms as onesforming the said ring, and optionally having one —NR²⁰—(R²⁰ is ahydrogen atom, a lower alkyl group, a phenyl group, a loweralkoxycarbonyl group, or a benzyl group) or one oxygen atom in the cyclethereof), or a group of the formula: —C(═O)NR⁴R⁵ (R⁴ and R⁵ are asdefined above)).

[0126] The divalent aliphatic hydrocarbon group having 1 to 15 carbonatoms and optionally having an unsaturated bond includes, for example,an alkylene chain having 1 to 6 carbon atoms, preferably having 1 to 4carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, etc., an alkenylene chain such aspropenylene, butenylene, etc., an alkynylene chain such as ethynylene,propynylene, butynylene, or as the group—E— an alkynylene chain such asan alkynylene of the following formula:

[0127] (R⁶ and R⁷ are independently a hydrogen atom, a methyl group, anethyl group or a propyl group, or R⁶ and R⁷ may combine each other toform a 3- to 7-membered cycloalkane ring, m is an integer of 0 to 6,preferably 0 or 1, and p is an integer of 0 to 6, preferably 0 or 1).

[0128] The 3- to 7-membered cycloalkane ring formed by combining R⁶ andR⁷ includes, for example, cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, etc.

[0129] The substituted aryl group for Q has one or more substituentswhich are the same or different, and the substituents are, for example,a halogen atom, a cyano group, a trifluoromethyl group, a nitro group, ahydroxy group, a methylenedioxy group, a lower alkyl group, a loweralkoxy group, a benzyloxy group, a lower alkanoyloxy group, an aminogroup, a mono-lower alkylamino group, a di-lower alkylamino group, acarbamoyl group, a lower alkylaminocarbonyl group, a di-loweralkylaminocarbonyl group, a carboxyl group, a lower alkoxycarbonylgroup, a lower alkylthio group, a lower alkylsulfinyl group, a loweralkylsulfonyl group, a lower alkanoylamino group, or a loweralkylsulfonamido group.

[0130] The heteroaryl group or the heteroaryl moiety of theheteroarylmethyl group include, for example, a 5- to 6-membered cyclicgroup having 1 to 3 nitrogen atoms, a 5-membered cyclic group having oneoxygen atom or one sulfur atom, or a bicyclic group formed by fusing a6-membered ring and a 5- or 6-membered ring, and having 1 to 4 nitrogenatoms, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-pyrrolyl,1-imidazolyl, 1,2,4-triazol-1-yl, 2-thienyl, 3-thienyl, 2-furyl,3-furyl, 2-quinolyl, etc.

[0131] The substituted heteroaryl group for Q has one or moresubstituents which are the same or different, and the substituents are,for example, a lower alkyl group, a lower alkoxy group, a halogen atom,etc.

[0132] The saturated cyclic amino group formed by NR⁴R⁵ includes, forexample, a group represented by the formula:

[0133] (wherein R²⁰ is a hydrogen atom, a lower alkyl group, a phenylgroup, a lower alkoxycarbonyl group, or a benzyl group) such as a4-lower alkyl-1-piperazinyl, 4-phenyl-1-piperazinyl,4-benzyl-1-piperazinyl, etc., or a monocyclic group such as1-pyrrolidinyl, 1-piperidinyl, 1-homopiperidinyl, 4-morpholinyl, etc.,or a bicyclic group such as 3-azabicyclo[3.2.2]nonane, etc.

[0134] The substituted alkyl group, the substituted cycloalkyl group,the substituted alkenyl group, and the substituted alkynyl group haveone or more substituents which are the same or different, and thesubstituents are, for example, a halogen atom, a cyano group, a phenoxygroup, a benzyloxy group, a trifluoromethyl group, a hydroxy group, alower alkoxy group, a lower alkanoyloxy group, an amino group, amono-lower alkylamino group, a di-lower alkylamino group, a carbamoylgroup, a lower alkylaminocarbonyl group, a di-lower alkylaminocarbonylgroup, a lower alkoxycarbonylamino group, a carboxyl group, a loweralkoxycarbonyl group, a lower alkylthio group, a lower alkylsulfinylgroup, a lower alkylsulfonyl group, a lower alkanoylamino group, a loweralkylsulfonamido group, a tri-lower alkylsilyl group, a phthalimidogroup, a heteroaryl group, a saturated heterocyclic group, or a group ofthe formula: —M²—E—Q (M² is an oxygen atom, a sulfur atom, or a group ofthe formula: —NR²¹ (R²¹ is a hydrogen atom or a lower alkyl group), Eand Q are as defined above).

[0135] The saturated heterocyclic group includes, for example, a 5- to8-membered cyclic group having one nitrogen atom, a 6- to 8-memberedcyclic group having two nitrogen atoms, and a 6- to 8-membered cyclicgroup having one nitrogen atom and one oxygen atom, such as1-piperidinyl, 1-pyrrolidinyl, etc.

[0136] The substituted alkyl group includes an alkyl group having 1 to 6carbon atoms which is substituted by a cycloalkyl group or a substitutedcycloalkyl group, or an aralkyl group or a substituted aralkyl group.

[0137] The aralkyl group or the substituted aralkyl group includes analkyl group having 1 to 6 carbon atoms which is substituted by theabove-mentioned aryl group or substituted aryl group, for example,benzyl, 1-phenylethyl, 2-phenylethyl, 2-naphthylmethyl, etc.

[0138] The phenylene group may be o-phenylene group, m-phenylene group,and p-phenylene group.

[0139] The term lower in the present invention means that alkyl moietydescribed with lower is a lower alkyl group, and including the caseswhen the lower alkyl group is a moiety of other substituents, the loweralkyl group may be an alkyl group having 1 to 6 carbon atoms such asmethyl, ethyl, propyl, 2-propyl, butyl, pentyl, hexyl, etc.

[0140] The halogen atom is fluorine atom, chlorine atom, bromine atom,and iodine atom.

[0141] The substituent of the substituted or unsubstituted alkyl groupfor R² may be, for example, lower alkoxy group.

[0142] The substituent of the substituted or unsubstituted phenyl groupfor R² may be, for example, a lower alkyl group, a lower alkoxy group,and a halogen atom.

[0143] The compounds of the formula (10) in the above [38] are novelcompounds which were found by the present inventors for the first time.In the compounds (10) in the above [38], preferable groups forexhibiting biological activities are exemplified below.

[0144] The preferable groups for Y¹ are, for example, a phenyl group orpyridyl group which may optionally be substituted. The substitutedphenyl group and the substituted pyridyl group have one or moresubstituents which are the same or different, and the preferablesubstituents are, for example, a halogen atom (e.g., fluorine atom,chlorine atom, etc.), a cyano group, a trifluoromethyl group, a nitrogroup, a hydroxy group, methylenedioxy group, a lower alkyl group, alower alkoxy group, a lower alkanoyloxy group, an amino group, amono-lower alkylamino group, a di-lower aIkylamino group, a carbamoylgroup, a lower alkylaminocarbonyl group, a di-lower alkylaminocarbonylgroup, a carboxyl group, a lower alkoxycarbonyl group, a lower alkylthiogroup, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a loweralkanoylamino group, a lower alkylsulfonamido group, or a group of theformula: —M¹—E—Q (M¹, E and Q are as defined above).

[0145] The preferable groups for E are, for example, a straightalkylene, alkenylene or alkynylene chain having 1 to 6 carbon atoms, andthe more preferable ones are a straight alkylene or alkynylene chainhaving 1 to 3 carbon atoms. The preferable groups for Q are, forexample, a hydroxy group, a halogen atom, a cyano group, a lower alkoxygroup, a lower alkanoyloxy group, a lower alkylthio group, a loweralkylsulfinyl group, a lower alkylsulfonyl group, a lower alkanoylaminogroup, a lower alkylsulfonamido group, a heteroaryl group, or a group ofthe formula: —NR⁴R⁵ (R⁴ and R⁵ are as defined above), and the morepreferable ones are a substituted or unsubstituted heteroaryl group(e.g., 2-pyridyl, 3-pyridyl, 2-methylpyridin-3-yl, 4-pyridyl,1-imidazolyl, 1,2,4-triazol-1-yl, etc.), or a group of the formula:—NR⁴R⁵ (R⁴ and R⁵ are as defined above). The preferable group of theformula: —NR⁴R⁵ (R⁴ and R⁵ are as defined above) includes, for example,dimethylamino, diethylamino, diisopropylamino, pyrrolidinyl,piperidinyl, morpholinyl, 4-methylpiperazinyl, etc.

[0146] The preferable group of the formula: —M¹—E—Q includes, forexample, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy,(2-methylpyridin-3-yl)methoxy, (2,4-dimethylpyridin-3 -yl)methoxy,2-hydroxyethoxy, 2-acetoxyethoxy, 2-(2-pyridyl)ethoxy,2-(3-pyridyl)ethoxy, 2-(4-pyridyl)ethoxy, 2-(diethylamino)ethoxy,2-(dimethylamino)ethoxy, 2-(piperidino)ethoxy, 2-(1-pyrrolidinyl)ethoxy,2-(morpholino)ethoxy, 2-(1,2,4-triazol-1-yl)ethoxy, 3-hydroxypropoxy,3-acetoxypropoxy, 3-(2-pyridyl)propoxy, 3-(3-pyridyl)propoxy,3-(4-pyridyl)propoxy, 3-(diethylamino)propoxy, 3-(dimethylamino)propoxy,3-(piperidino)propoxy, 3-(1-pyrrolidinyl)propoxy, 3-(morpholino)propoxy,2-(1,2,4-triazol-1-yl)-propoxy, 3-dimethylamino-1-propynyl,3-diethylamino-1-pyropynyl, 3-(1-pyrrolidinyl)-1-propynyl,3-(N-methyl-N-(3-pyridylmethyl)amino)-1-propynyl,2-(diethylamino)ethylthio, N-methyl-N-(3-pyridylmethyl)amino,3-(diethylamino)propyl, etc.

[0147] The preferable groups for L are a phenyl or heteroaryl groupwhich may optionally be substituted, and the more preferable groups forL are a phenyl or pyridyl group which is substituted by 1 to 3 groupsselected from a group consisting of a halogen atom (e.g., a fluorineatom, chlorine atom, etc.), a lower alkyl group, a lower alkoxy groupand a lower alkylthio group, or a phenyl group substituted by a loweralkyl group and a group of the formula: —M¹—E—Q (M¹, E and Q are asdefined above). The preferable groups for E are, for example, a straightalkylene, alkenylene or alkynylene chain having 1 to 6 carbon atoms, andthe more preferable ones are a straight alkylene or alkynylene chainhaving 1 to 3 carbon atoms.

[0148] The preferable groups for Q are, for example, a hydroxy group, aheteroaryl group, or a group of the formula: —NR⁴R⁵ (R⁴ and R⁵ are asdefined above), and the more preferable ones are a substituted orunsubstituted heteroaryl group (e.g., 2-pyridyl, 3-pyridyl,2-methylpyridin-3-yl, 4-pyridyl, 1-imidazolyl, 2-isopropyl-1-imidazolyl,1-pyrazolyl, 1,2,4-triazol-1-yl, etc.), or a group of the formula:—NR⁴R⁵ (R⁴ and R⁵ are as defined above).

[0149] The preferable group of the formula: —NR⁴R⁵ (R⁴ and R⁵ are asdefined above) includes, for example, dimethylamino, diethylamino,diisopropylamino, pyrrolidinyl, piperidinyl, morpholinyl,4-methylpiperazinyl, etc.

[0150] The preferable groups for L are, for example,2,6-diisopropylphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl,2,4-difluorophenyl, 2,4,6-trifluorophenyl,2-tert-butyl-5-(morpholinomethyl)phenyl, 2-tert-butyl-5-(2-isopropyl-l-imidazolyl)phenyl, 2-tert-butyl-5-(1-pyrazolyl)phenyl,2-tert-butyl-5-{N-methyl-N-(2-pyridylmethyl)aminomethyl}phenyl,2-tert-butyl-5-{N-methyl-N-(3-pyridylmethyl)aminomethyl}phenyl,2-tert-butyl-5-{N-methyl-N-(4-pyridylmethyl)aminomethyl}phenyl,2,4-bis(methylthio)pyridin-3-yl,2-tert-butyl-5-{N-ethyl-N-(3-pyridylmethyl)aminomethyl}phenyl,2,4-bis(methylthio)-6-methylpyridin-3-yl, etc.

[0151] The acid for forming an acid addition salt includes, for example,inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, nitric acid, sulfuric acid, etc., or organic acids such as aceticacid, oxalic acid, citric acid, malic acid, tartaric acid, fumaric acid,maleic acid, methanesulfonic acid, etc.

[0152] When the compounds of the present invention have an acidic groupsuch as carboxyl group, then the present compounds may be in the form ofa salt with an organic base (e.g., diethanolamine salt, ethylenediaminesalt, N-methylglucamine salt), a salt with an alkaline earth metal(e.g., calcium salt, magnesium salt), or a salt with an alkali metal(e.g., lithium salt, potassium salt, sodium salt).

[0153] The compounds of the present invention may have a stereoisomerdue to an asymmetric carbon atom thereof. In such cases, the presentcompounds also include each isomer or a mixture thereof.

[0154] The present compounds and a salt thereof may be in the form of ananhydrous product thereof, or in the form of a solvate thereof such ashydrate.

[0155] The compounds of the above-mentioned formula (10) or a saltthereof can be administered either parenterally or orally when used asthe above-mentioned drug. The present compounds can be formulated intoliquid preparations such as solutions, emulsions, suspensions, etc., andcan be administered in the form of an injection, and if necessary,buffering agents, solubilizers and isotonic agents may be added thereto.The present compounds can also be administered rectally in the form of asuppository. The present compounds can also be administered orally inthe form of a conventional administration form such as tablets,capsules, syrups, and suspension. These pharmaceutical preparations canbe formulated by mixing an active ingredient with conventional carriersor diluents, binding agents or stabilizers by a conventional manner.

[0156] The dosage and the frequency of administration of the presentcompounds may vary according to the conditions, ages, weights of thepatients and the administration form, etc., but when the presentcompound is administered orally, the daily dosage thereof is in therange of 1 to 500 mg for an adult, once a day, or divided into 2-4dosage units.

[0157] Processes [1] to [37] and the processes for preparing thecompounds [38] to [54] will be described in detail. In the descriptionof the present processes, the compounds used therein have an reactivegroup such as amino group, alkylamino group, lower alkylamino group,hydroxy group, carboxyl group as a substituent, then these groups mayoptionally be protected or deprotected to give the desired compounds.

[0158] The protecting groups for amino group, alkylamino group, loweralkylamino group, hydroxy group, carboxyl group, etc., may beconventional protecting groups which are used in the field of theorganic chemistry (e.g., the protecting group for hydroxy group may bebenzyl group or acetyl group: the protecting group for amino group maybe benzyl group, etc.), and these protecting groups may be introduced orremoved by a conventional method, as described in PROTECTIVE GROUPS INORGANIC SYNTHESIS, 2nd ed., John Wiley & Sons, Inc.; New York.

[0159] wherein L is an alkyl group, a substituted alkyl group, analkenyl group, a substituted alkenyl group, a cycloalkyl group, asubstituted cycloalkyl group, an aromatic group, or a substitutedaromatic group; Ring B is a substituted or unsubstituted benzene ring;R¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, analkenyl group, a substituted alkenyl group, an alkynyl group, asubstituted alkynyl group, a cycloalkyl group, or a substitutedcycloalkyl group; R² is a substituted or unsubstituted lower alkylgroup, or a substituted or unsubstituted phenyl group; R¹⁰ is a loweralkyl group; X is a chlorine atom or a bromine atom; Y¹ is a hydrogenatom, an alkyl group, a substituted alkyl group, a cycloalkyl group, asubstituted cycloalkyl group, an aromatic group, or a substitutedaromatic group; and Y² and Y³ are independently a hydrogen atom, ahalogen atom, a hydroxy group, a cyano group, a trifluoromethyl group, anitro group, an amino group, a mono-lower alkylamino group, a di-loweralkylamino group, a lower alkoxy group, a lower alkylthio group, a loweralkylsulfinyl group, a lower alkylsulfonyl group, an allyl group, asubstituted alkyl group, a cycloalkyl group, a substituted cycloalkylgroup, an aromatic group, a substituted aromatic group, or Y² and Y³ maycombine each other together with the carbon atoms to which they bond,and form a substituted or unsubstituted pyridine ring.

[0160] a) Step from the compound (15) to the compound (1):

[0161] The carbamoylpyridone derivative of the formula (1) canpreferably be obtained by reacting the ester derivative of the formula(15) with formaldehyde in an amount of 1 to 10 mole equivalents,preferably in an amount of 2 to 7 mole equivalents, in the presence of abase (e.g., an alkali metal salt of alcohol such as sodium methoxide,sodium ethoxide, or an alkali metal ammonia such as sodium amide) in anamount of 1 to 10 mole equivalents, preferably in an amount of 2 to 7equivalents, in a solvent at a temperature of from room temperature to100° C., preferably at a temperature of from 50° C. to 80° C. Thesolvent may be any solvent which does not disturb the reaction, forexample, ethers (e.g., dimethoxyethane, tetrahydrofuran, dioxane, etc),aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.),halogenated hydrocarbons (e.g., chloroform, dichloroethane,chlorobenzene, dichlorobenzene, etc.), and amides (e.g.,N,N-dimethyl-formamide, N,N-dimethylacetamide, etc.). The preferablesolvent is N,N-dimethylformamide. The amide derivative (1) can be alsoobtained by treating the ester derivative (15) with an excess amount ofliquid ammonia in a solvent or without solvent at a temperature of from0° C. to 120° C., preferably at a temperature of from room temperatureto 60° C., and if necessary, under pressure using an autoclave. Thesolvent is usually methanol.

[0162] b) Step from the compound (16) to the compound (1):

[0163] The carbamoylpyridone derivative of the formula (1) can be alsoprepared by converting the carboxylic acid derivative (16) to an acidhalide (e.g., an acid chloride or acid bromide) thereof, and reactingwith ammonia. The solvent may be any solvent which does not disturb thereaction, for example, ethers (e.g., diethyl ether, dimethoxyethane,tetrahydrofuran, dioxane, etc), aromatic hydrocarbons (e.g., benzene,toluene, xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane,chloroform, dichloroethane, chlorobenzene, dichlorobenzene, etc.), andamides (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, etc.). Theconversion to an acid halide may be carried out by a conventionalmethod, for example, an acid chloride can preferably be obtained byreacting with thionyl chloride in an amount of 1 to 3 mole equivalentsat a temperature of from 50° C. to 80° C. in an aromatic hydrocarbons(e.g., benzene, toluene, etc.). The reaction with ammonia is carried outby a conventional method, for example, by reacting with conc. aqueousammonia in a solvent at a temperature of from −10° C. to 60° C.,preferably at a temperature of from 0° C. to 30° C. The solvent may beany solvent which does not disturb the reaction, for example, ethers(e.g., diethyl ether, dimethoxyethane, tetrahydrofuran, dioxane, etc),aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.),halogenated hydrocarbons (e.g., dichloromethane, chloroform,dichloroethane, chlorobenzene, dichlorobenzene, etc.), and amides (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide, etc.).

[0164] c) Steps from the compound (1) to the compound (4), and from thecompound (5) to the compound (4):

[0165] The 2-carbamoylpyridone derivative (1) is reacted with leadtetraacetate in an amount of 1 to 3 mole equivalents, preferably in anamount of 1 to 1.5 mole equivalent in a solvent at a temperature of from0° C. to 80° C., preferably at a temperature of from room temperature to60° C., to give the isocyanate derivative (2). The solvent may be anysolvent which does not disturb the reaction, for example, aromatichydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenatedhydrocarbons (e.g., dichloromethane, dichloroethane, etc.), and amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide, etc.). Thepreferable solvent is N,N-dimethylformamide. The isocyanate derivative(2) thus obtained may be isolated and subjected to the subseqentreaction into a new solvent, or alternatively the reaction mixture maybe used in the subsequent reaction without isolation of the isocyanatederivative (2), the reaction is carried out with the amine derivative(3) in an amount of 1 to 3 mole equivalents, preferably in an amount of1 to 1.5 mole equivalents at a temperature of from 0° C. to 120° C.,preferably at a temperature of from room temperature to 60° C., up to aboiling point of the solvent, to give the 2-pyridone derivative (4). Thesolvent may be any solvent which does not disturb the reaction, forexample, ethers (e.g., diethyl ether, dimethoxyethane, tetrahydrofuran,dioxane, etc), aromatic hydrocarbons (e.g., benzene, toluene, xylene,etc.), esters (e.g., ethyl acetate, propyl acetate, etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, dichloroethane,chlorobenzene, dichlorobenzene, etc.), ketones (e.g., acetone, methylethyl ketone, etc.), nitrites (e.g., acetonitrile, isobutyronitrile,etc.), and amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamide,etc.). The preferable solvent is aromatic hydrocarbons (e.g., benzene,toluene, etc.), halogenated hydrocarbons (e.g., dichloromethane,dichloroethane, etc.), and amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide, etc.). Especially preferable solvent isN,N-dimethylformamide.

[0166] When the amine derivative (3) is used in the form of an acidaddition salt thereof, the reaction may smoothly proceed by convertingthe compound (3) into a free form, if necessary. In this case, an agentfor converting the compound (3) into a free form is preferably atertiary amine such as triethylamine, etc., or pyridine, etc.

[0167] On the other hand, the carbamoylpyridone derivative (1) isconverted into the isocyanate derivative (2) by reacting it with ahypochlorite or a hypobromite in an amount of 1 to 10 mole equivalents,preferably in an amount of 1 to 5 mole equivalent in a mixed solvent ofwater and an organic solvent at a temperature of from 0° C. to 80° C.,preferably at a temperature of from room temperature to 50° C., and thenfurther reacted with the amine derivative (3) in an amount of 1 to 3mole equivalents, preferably in an amount of 1 to 1.5 mole equivalent,to give the pyridone derivative (4). When the isocyanate derivative (2)is prepared, the reaction may proceed quickly by addition of a phasetransfer catalyst in an amount of 0.05 to 0.2 mole equivalent. The phasetransfer catalyst is preferably tetrabutylammonium hydrogen sulfate. Thepreferable hypochlorite or hypobromite is sodium hypobromite. The sodiumhypobromite is usually prepared from aqueous sodium hydroxide solutionand bromine at 0° C. to 10° C. in the reaction system. The organicsolvent may be any solvent which does not disturb the reaction, forexample, ethers (e.g., dimethoxyethane, tetrahydrofuran, dioxane, etc),aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.),halogenated hydrocarbons (e.g., dichloromethane, chloroform,dichloroethane, chlorobenzene, dichlorobenzene, etc.), and amides (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide, etc.). When the isocyanatederivative (2) is reacted with the amine derivative (3), the yield ofthe reaction may be improved by addition of acetic acid in a volume of10 to 30% of the volume of the reaction solvent.

[0168] The compound (5) and the compound (31) are reacted in the samemanner as in the above reaction of the compound (2) and the compound (3)to give the compound (4). The compound (31) is disclosed in literaturesor may be prepared by a conventional method for preparation of anisocyanate as disclosed in literatures. Besides, in the same manner asin the preparation of the compound (2) from the compound (1), thecompound (31) can be prepared from a compound of the formula (33):

L—CONH₂  (33)

[0169] which is disclosed in literatures or may be prepared by aconventional method for preparation of an amide compound.

[0170] d) Step from the compound (1) to the compound (5):

[0171] The carbamoylpyridone derivative (1) is reacted with ahypochlorite or hypobromite in an amount of 1 to 10 mole equivalents,preferably in an amount of 1 to 5 mole equivalents in a mixed solvent ofwater and an organic solvent at a temperature of from 0° C. to 80° C.,preferably at a temperature of from room temperature to 50° C., and theresulting isocyanate derivative (2) is subjected to hydrolysis to givethe aminopyridone derivative (5). By addition of a phase transfercatalyst in an amount of 0.05 to 0.2 mole equivalent in the step ofproduction of the isocyanate derivative, the reaction may quicklyproceed. The phase transfer catalyst is preferably tetrabutylammoniumhydrogen sulfate. The hydrolysis is usually carried out by subsequentlystirring the reaction mixture containing the compound (2) at 30° C. to50° C. The preferable hypochlorite or hypobromite is, for example,sodium hypobromite. The sodium hypobromite is usually prepared from anaqueous sodium hydroxide solution and bromine at 0° C. to 10° C. Thesolvent may be any solvent which does not disturb the reaction, forexample, ethers (e.g., diethyl ether, dimethoxyethane, tetrahydrofuran,dioxane, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene,etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform,dichloroethane, chlorobenzene, dichlorobenzene, etc.), and amides (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide, etc.). The preferablesolvent is, for example, tetrahydrofuran and toluene.

[0172] The carbamoylpyridone derivative (1) can be converted into theaminopyridone derivative (5) by Hofmann reaction. The Hofmann reactionis carried out by reacting with a hypochlorite or a hypobromite in anamount of 1 to 3 mole equivalents, preferably in an amount of 1 to 1.5mole equivalent in a solvent at a temperature of from 0° C. to 80° C.,preferably at a temperature of from room temperature to 50° C. Thehypochlorite or hypobromite is usually sodium hypobromite. The solventmay be any solvent which does not disturb the reaction, for example,ethers (e.g., diethyl ether, dimethoxyethane, tetrahydrofuran, dioxane,etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.),halogenated hydrocarbons (e.g., dichloromethane, chloroform,dichloroethane, chlorobenzene, dichlorobenzene, etc.), and amides (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide, etc.).

[0173] e) Step from the compound (5) to the compound (4):

[0174] The aminopyridone derivative (5) is reacted with a halocarbonate(6) in an amount of 1 to 10 mole equivalents, preferably in an amount of1 to 3 mole equivalents, at a temperature of from room temperature to aboiling point of the solvent, preferably at a temperature of from roomtemperature to 80° C., and the resulting carbamic acid ester derivative(7) is reacted with the amine derivative (3) in an amount of 1 to 5 moleequivalents, preferably 1 to 2 mole equivalents at a temperature of fromroom temperature to a boiling point of the solvent, preferably at atemperature of from room temperature to 100° C., in the presence of4-dimethylaminopyridine in an amount of 1 to 3 mole equivalents,preferably in an amount of 1 to 1.5 mole equivalent, to give thepyridone derivative (4). The preferable halocarbonate is phenylchlorocarbonate. The reaction is usually carried out in a solvent, andthe solvent may be any solvent which does not disturb the reaction, forexample, ethers (e.g., isopropyl ether, tetrahydrofuran, dioxane, etc.),aromatic hydrocarbons (e.g., benzene, toluene, etc.), esters (e.g.,methyl acetate, ethyl acetate, etc.), halogenated solvents (e.g.,dichloromethane, chloroform, etc.), and N,N-dimethylformamide,dimethylsulfoxide, etc. The reaction may be promoted by addition of abase. The base includes, for example, sodium carbonate, potassiumcarbonate, triethylamine, pyridine, N,N-dimethylaniline, etc.

[0175] wherein R¹, R²,Y¹, Y², Y³ and L are as defined above.

[0176] Alternatively, in the same manner as in the preparation of thecarbamic acid ester derivative (7) from the amine derivative (5) asmentioned above, the carbamic acid ester derivative (32) is obtainedfrom the amine derivative (3) and the halocarbonate (6) in an amount of1 to 10 mole equivalents, preferably in an amount of 1 to 3 moleequivalents, and said compound (32) is reacted with the amine derivative(5) in the same manner as in the preparation of the pyridone derivative(4) from the amine derivative (7) as mentioned above, to give thepyridone derivative (4).

[0177] f) Step from the compound (17) to the compound (8):

[0178] The aminoketone derivative (17). is reacted with an acid halideof N-phthaloylglycine of the formula (18) in an amount of 1 to 5 moleequivalents, preferably in an amount of 1 to 2.5 mole equivalents, in asolvent, at a temperature of from room temperature to 100° C.,preferably at a temperature of from room temperature to 80° C., to givethe amide derivative (8). The reaction is preferably carried out byaddition of a base in an amount of 1 mole equivalent or more. The baseincludes, for example, a tertiary amine such as triethylamine, orpyridine. The solvent may be any solvent which does not disturb thereaction, for example, ethers (e.g., dimethoxyethane, tetrahydrofuran,dioxane, etc), aromatic hydrocarbons (e.g., benzene, toluene, xylene,etc.), esters (e.g., ethyl acetate, propyl acetate, etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, dichloroethane,chlorobenzene, dichlorobenzene, etc.), nitrites (e.g., acetonitrile,isobutyronitrile, etc.), and amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide, etc.). The preferable solvent may be aromatichydrocarbons such as benzene, toluene, etc. The amide derivative (8) canusually be used in the subsequent reaction without further purification.Moreover, the reaction mixture containing the amide derivative (8) canalso be used in the subsequent reaction.

[0179] g) Step from the compound (8) to the compound (9):

[0180] Subsequently, the amide derivative (8) is subjected tocyclization reaction by heating it in a solvent in the presence of abase in an amount of 1 to 20 mole equivalents, preferably in an amountof 1 to 7 mole equivalents, at 50-120° C., preferably at 70-110° C., togive the 1,2-dihydro-2-pyridone derivative (9). The compound (9) isusually used in the subsequent reaction without further purification.The base is preferably an alkali metal carbonate such as sodiumcarbonate, potassium carbonate, etc. The solvent may be aromatichydrocarbons (e.g., benzene, toluene, xylene, etc.), and amides (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide, etc.). The preferablesolvent is N,N-dimethylacetamide.

[0181] h) Step from the compound (9) to the compound (5):

[0182] The 3-aminopyridone derivative (5) is prepared by removing theprotecting phthaloyl group of the 1,2-dihydro-2-pyridone derivative (9).The removal of the protecting phthaloyl group may be carried out by aconventional method which is usually used in the field of the organicchemistry, for example, as described in PROTECTIVE GROUPS IN ORGANICSYNTHESIS, 2nd ed., John Wiley & Sons, Inc.; New York. The preferablemethod of deprotection is a method of adding an excess amount of analcohol solution or aqueous solution of a lower alkylamine (e.g.,methylamine) at 0-50° C., preferably at room temperature, to thereaction system wherein the compound (9) is produced.

[0183] i) Step of preparing the compound (17):

[0184] The aminoketone derivative (17) wherein R¹ is a hydrogen atom,i.e., the derivative (19) may be prepared by the method disclosed in theliterature (e.g., J. Heterocyclic Chem., 2, 105-112, 1989; J.Heterocyclic Chem., 13, 1283-1288, 1976) or a modified method thereof.In addition, the aminoketone derivative (17) wherein R¹ is a group otherthan a hydrogen atom may be prepared by the following Reaction Scheme.

[0185] wherein Y¹, Y² and Y³ are as defined above, R¹¹ is an alkylgroup, a substituted alkyl group, an alkenyl group, a substitutedalkenyl group, an alkynyl group, a substituted alkynyl group, acycloalkyl group, or a substituted cycloalkyl group, and G is a leavinggroup.

[0186] The aminoketone derivative (19) is reacted with an alkylatingagent (20) in the presence of a base at a temperature of from 0° C. to150° C., preferably at a temperature of from room temperature to 80° C.in a solvent to give the compound (21). The solvent may be alcohols(e.g., methanol, ethanol, etc.), ethers (e.g., tetrahydrofuran, dioxane,etc.), ketones (e.g., acetone, 2-butanone, etc.), dimethylformamide,etc. The base may be an alkali metal hydroxide (e.g., sodium hydroxide,potassium hydroxide, etc.), an alkali metal alcoholate (e.g., sodiummethoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metalhydride (e.g., sodium hydride, etc.), an alkali metal carbonate (e.g.,potassium carbonate, sodium carbonate, etc.), and an organic base (e.g.,triethylamine). The leaving group for G is usually a halogen atom suchas chlorine, bromine, iodine, etc., or aromatic sulfonyloxy group suchas p-toluenesulfonyloxy group.

[0187] The ester derivative (15) and the carboxylic acid derivative (16)may be prepared by the method disclosed in the literature (e.g.,JP-A-9-48780; Australian J. Chem., 1983, 36, 1431; J. Chem. Soc., 1908,1022; J. Chem. Soc., 1904, 1726; J. Chem. Soc., 1915, 792; J. Am. Chem.Soc., 1956, 78, 4683), or a modified method thereof.

[0188] The present compound (10) wherein Z is a direct bond may beprepared by the following method.

[0189] wherein L, R¹, Y¹, Y²² and Y³² are as defined above.

[0190] The amine derivative (24) or an acid addition salt thereof iscondensed with the carboxylic acid derivative (25) using a condensingagent in a solvent at a temperature of from 0° C. to 100° C., preferablyat a temperature of from 0° C. to 60° C., and if necessary, theresultant is further subjected to deprotection reaction to give theamide derivative (11). The condensing agent may bedicyclohexylcarbodiimide (DCC), N,N′-carbodiimidazole, diethylcyanophosphate (DEPC), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimidehydrochloride (WSC), etc. The reaction may preferably proceed byaddition of a base in an amount of 1 to 5 mole equivalents, preferablyin an amount of 1 to 3 mole equivalents, to the amount of the aminederivative (24) or an acid addition salt thereof. The base may be atertiary amine such as triethylamine, diisopropylethylamine, orpyridine, etc. The solvent may be any solvent which does not disturb thereaction, for example, ethers (e.g., diethyl ether, dimethoxyethane,tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (e.g., benzene,toluene, xylene, etc.), esters (e.g., ethyl acetate, propyl acetate,etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform,dichloroethane, chlorobenzene, dichlorobenzene, etc.), ketones (e.g.,acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile,isobutyronitrile, etc.), and amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide, etc.).

[0191] Alternatively, the carboxylic acid derivative (25) is convertedinto a reactive derivative thereof, which is further reacted with theamine derivative (24) in a solvent at a temperature of from −10° C. to120° C., preferably at a temperature of from 0° C. to 60° C. to give theamide derivative (26). The reactive derivative of the carboxylic acidderivative (25) may be, for example, an acid chloride, an acid bromide,an acid anhydride, or a mixed acid anhydride with methyl carbonate,ethyl carbonate, or the like, and the reaction may preferably proceed byaddition of a base in an amount of 1 to 5 mole equivalents, preferablyin an amount of 1 to 3 mole equivalents. The base may be a tertiaryamine (e.g., triethylamine), pyridine, an alkali metal carbonate (e.g.,sodium carbonate, potassium carbonate), and an alkali metal hydrogencarbonate (e.g., sodium hydrogen carbonate). The solvent may be anysolvent which does not disturb the reaction, for example, ethers (e.g.,diethyl ether, dimethoxyethane, tetrahydrofuran, dioxane, etc.),aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), esters(e.g., ethyl acetate, propyl acetate, etc.), halogenated hydrocarbons(e.g., dichloromethane, chloroform, dichloroethane, chlorobenzene,dichlorobenzene, etc.), ketones (e.g., acetone, methyl ethyl ketone,etc.), nitrites (e.g., acetonitrile, isobutyronitrile, etc.), and amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide, etc.).

[0192] Some of the present compounds (10) wherein Z is —NH— can also beprepared by the following method.

[0193] wherein L, R¹¹, Y¹, Y²², Y³² and G are as defined above.

[0194] The urea derivative (22) is converted into the urea derivative(23) by reacting with an alkylating agent (20). The alkylation reactionis carried out in a solvent at a temperature of from 0° C. to 100° C.,preferably at a temperature of from room temperature to 70° C. in thepresence of a base. The solvent may be, for example, ethers (e.g.,tetrahydrofuran, dioxane, etc.), ketones (e.g., acetone, 2-butanone,etc.), aromatic hydrocarbons (e.g., benzene, toluene, etc.), anddimethyl-formamide. The base may be sodium hydride, potassium carbonate,sodium carbonate, triethylamine, etc. The leaving group for G is usuallya halogen atom (e.g., chlorine, bromine, iodine, etc.) or an aromaticsulfonyloxy group (e.g., p-toluenesulfonyloxy group).

[0195] The substituents for L, R¹, Y¹, Y²² and Y³² of the pyridonederivative (10) can be converted each other, if necessary. For example,a lower alkylthio group can be converted into a lower alkylsulfonylgroup by oxidation, a nitro group can be converted into an amino groupby reduction reaction, an amino group can be converted into a mono- ordi-alkyl group by alkylation, or an amino group can be acylated.Further, a 3-chloropropoxy group is converted into a3-(1-imidazolyl)-propoxy group. In addition, a halogen atom such asbromine, iodine can be converted into a 1-propargyl group having ahydroxy group or an amino group at the 3-position by using a palladiumcatalyst. Said propargyl group can be further converted into a propylgroup by hydrogenation reaction. Such conversion reactions of thesubstituents can be carried out by a conventional technique which isusually used in the field of the organic chemistry.

[0196] The alkylation reaction as shown in the following scheme may becarried out as one of these conversion reactions of substiuents.

[0197] wherein G, E, Z, L, R¹¹, Y²², Y³² and Q are as defined above, M²is an oxygen atom, a sulfur atom or a group of the formula: —NR²¹—(R²¹is as defined above).

[0198] The compound (27) is reacted with the alkylating agent (28) in asolvent, and if necessary, followed by deprotection to give the compound(29). The reaction is usually carried out in a solvent at a temperatureof from 0° C. to 100° C., preferably at a temperature of from roomtemperature to 70° C., in the presence of a base. The solvent may be,for example, ethers (e.g., tetrahydrofuran, dioxane, etc.), aromatichydrocarbons (e.g., benzene, toluene, etc.), ketones (e.g., acetone,methyl ethyl ketone, etc.), and dimethylformamide. The base may be, forexample, sodium hydride, potassium carbonate, sodium carbonate,triethylamine, etc. When potassium carbonate or sodium carbonate isused, the yield may be improved by addition of sodium iodide orpotassium iodide. The leaving group for G is usually a halogen atom(e.g., chlorine, bromine, iodine, etc.) or an aromatic sulfonyloxy group(e.g., p-toluenesulfonyloxy group).

[0199] The intermediate (2) or (5) of the present invention may beprepared, for example, by the method as disclosed below or a modifiedmethod thereof.

[0200] wherein R¹, R¹¹, Y¹, Y², Y³ and G are as defined above, and R¹⁰is a lower alkyl group.

[0201] The starting compound (30) may be prepared by the methoddisclosed in the literature (e.g., JP-A-9-48780; Australian J. Chem.,1983, 36, 1431; J. Chem. Soc., 1908, 1022; J. Chem. Soc., 1904, 1726; J.Chem. Soc., 1915, 792; J. Am. Chem. Soc., 1956, 78, 4683) or a modifiedmethod thereof. The lower alkyl group for R¹⁰ is preferably an alkylgroup having 1 to 4 carbon atoms such as methyl, ethyl, propyl,isopropyl, butyl, etc.

[0202] The ester derivative (30) is converted into the compound (15) byalkylation reaction, if necessary. The alkylation reaction is carriedout by reacting with the alkylating agent (20) in a solvent at atemperature of from 0° C. to 150° C., preferably at a temperature offrom room temperature to 80° C., in the presence of a base. The solventmay be alcohols (e.g.. methanol, ethanol, etc.), ethers (e.g.,tetrahydrofuran, dioxane, etc.), ketones (e.g., acetone, 2-butanone,etc.), and dimethyl-formamide. The base may be sodium hydroxide,potassium hydroxide, sodium methoxide, sodium ethoxide, potassiumt-butoxide, sodium hydride, potassium carbonate, sodium carbonate,triethylamine, etc. The leaving group for G is usually a halogen atom(e.g. chlorine, bromine, iodine, etc.) or an aromatic sulfonyloxy group(e.g., p-toluene-sulfonyloxy group, etc.).

[0203] Subsequently, the compound (15) is subjected to hydrolysis togive the carboxylic acid derivative (16). The hydrolysis is carried outby a conventional method, for example, by using a hydroxide of an alkalimetal or alkaline earth metal (e.g., sodium hydroxide, potassiumhydroxide, barium hydroxide, etc.), in a solvent (e.g., methanol,ethanol, isopropanol, tetrahydrofuran, dioxane, dimethoxyethane, etc.)at a temperature of from 0° C. to 150° C., preferably at a temperatureof from 0° C. to 100° C. The carboxylic acid derivative (16) isconverted into an acid azide thereof by using an azidating agent (e.g.,diphenyl-phosphorylazide (DPPA), etc.) in an amount of 1 to 3 moleequivalents, in a solvent in the presence of a base (e.g.,triethylamine, N-methyl-morpholine, etc.) at a temperature of from 0° C.to 120° C., preferably at a temperature of from room temperature to 80°C., and the resulting acid azide compound is usually heated at atemperature of from 20° C. to 150° C., preferably at a temperature offrom 30° C. to 100° C. without isolation from the reaction system, togive the compound (2). Moreover, in the same manner as in the hydrolysisof the compound (15), the compound (2) is subjected to hydrolysis togive the compound (5).

[0204] The compounds of the present invention prepared by the presentmethods and the intermediates thereof may be purified by a conventionalmethod, for example, column chromatography, recrystallization, etc. Thesolvent for recrystallization may properly be selected from alcohols(e.g., methanol, ethanol, 2-propanol, etc.), ethers (e.g., diethylether, etc.), esters (e.g., ethyl acetate, etc.), aromatic solvents(e.g., toluene, etc.), ketones (e.g., acetone, etc.), hydrocarbons(e.g., hexane, etc.) or a mixture of these solvent.

[0205] The compounds of the present invention prepared by the aboveProcesses are listed below. The abbreviation used in Tables 1 to 12 isshown. That is, Imd denotes 1-imidazolyl group, 2-Me—Imd denotes2-methyl-1-imidazolyl group, Pyrz denotes 1-pyrazolyl group, Triazdenotes 1,2,4-triazol-1-yl group, Morp denotes morpholino group, Quindenotes quinolyl group, Py denotes pyridyl group, Pipe denotespiperidino group, Pyrro denotes 1-pyrrolidinyl group, Pipera denotes1-piperazinyl group, Phe denotes phenyl group, Me denotes methyl group,Et denotes ethyl group, Pr denotes propyl group, iPr denotes isopropylgroup, Bu denotes butyl group, tBu denotes tert-butyl group, Hex denoteshexyl group, cHex denotes cyclohexyl group, and Bn denotes benzyl group,respectively. TABLE 1

Y¹ Y² Y³ R¹ L Me H H Bu 2,6-di-iPr-Phe Et H H Bu 2,6-di-iPr-Phe Pr H HBu 2,6-di-iPr-Phe iPr H H Bu 2,6-di-iPr-Phe Bu H H Bu 2,6-di-iPr-Phe(CH₂)₉CH₃ H H Bu 2,6-di-iPr-Phe (CH₂)₁₀CH₃ H H Bu 2,6-di-iPr-Phe(CH₂)₁₄CH₃ H H Bu 2,6-di-iPr-Phe Ph H H Bu 2,6-di-iPr-Phe 2-Py H H Bu2,6-di-iPr-Phe 3-Py H H Bu 2,6-di-iPr-Phe 4-Py H H Bu 2,6-di-iPr-Phe HPh H Bu 2,6-di-iPr-Phe H H Ph Bu 2,6-di-iPr-Phe H H Ph H 2,6-di-iPr-PheH H Ph Me 2,6-di-iPr-Phe H H Ph Et 2,6-di-iPr-Phe H H Ph Pr2,6-di-iPr-Phe H H Ph iPr 2,6-di-iPr-Phe

[0206] TABLE 2

A¹ A² A³ A⁴ Y² Y³ R¹ L MeO H H H H H H 2,6-di-iPr-Phe MeO H H H H H Me2,6-di-iPr-Phe MeO H H H H H Et 2,6-di-iPr-Phe MeO H H H H H Pr2,6-di-iPr-Phe MeO H H H H H iPr 2,6-di-iPr-Phe MeO H H H H H Bu2,6-di-iPr-Phe MeO H H MeO H H H 2,6-di-iPr-Phe MeO H H MeO H H Me2,6-di-iPr-Phe MeO H H MeO H H Et 2,6-di-iPr-Phe MeO H H MeO H H Pr2,6-di-iPr-Phe MeO H H MeO H H iPr 2,6-di-iPr-Phe MeO H H MeO H H Bu2,6-di-iPr-Phe EtO H H MeO H H Bu 2,6-di-iPr-Phe PrO H H MeO H H Bu2,6-di-iPr-Phe iPrO H H MeO H H Bu 2,6-di-iPr-Phe MeO H H MeO Me H Bu2,6-di-iPr-Phe MeO H MeO H H H Bu 2,6-di-iPr-Phe MeO MeO H H H H Bu2,6-di-iPr-Phe MeO H H Me H H Bu 2,6-di-iPr-Phe MeO H H F H H Bu2,6-di-iPr-Phe MeO H H Cl H H Bu 2,6-di-iPr-Phe MeO H H Br Me H Bu2,6-di-iPr-Phe MeO H H Br H H Bu 2,6-di-iPr-Phe

[0207] TABLE 3

A¹ A⁵ Y² Y³ R¹ L MeO CH₂-3-Py H H Bu 2-iPr-Phe MeO CH₂-3-Py H H Bu2,6-di-iPr-Phe MeO CH₂-3-Py H H Bu 2-Me-Phe MeO CH₂-3-Py H H Bu2,6-di-Me-Phe MeO CH₂-3-Py H H Bu 2,4,6-tri-Me-Phe MeO CH₂-3-Py H H Bu2-F-Phe MeO CH₂-3-Py H H Bu 2,6-di-F-Phe MeO CH₂-3-Py H H Bu2,4,6-tri-F-Phe MeO CH₂-3-Py H H Bu 2-iPr-Phe MeO CH₂-3-Py H H Bu2-iPr-6-Me-Phe MeO CH₂-3-Py H H Bu 2-Et-Phe MeO CH₂-3-Py H H Bu2,6-di-Et-Phe MeO CH₂-3-Py H H Bu 2-iPr-6-Me-Phe MeO CH₂-3-Py H H Bu2-Et-6-iPr-Phe MeO CH₂-3-Py H H Bu 2-Me-6-tBu-Phe MeO CH₂-3-Py H H Bu2,4,6-tri-MeO-Phe MeO CH₂-3-Py H H Bu 2-EtO-Phe MeO CH₂-3-Py H H Bu2-MeS-Phe MeO CH₂-3-Py H H Bu 2-CF₃-Phe MeO CH₂-3-Py H H Bu 2-Br-Phe MeOCH₂-3-Py H H Bu 2,6-di-Br-Phe MeO CH₂-3-Py H H Bu 2-Cl-Phe MeO CH₂-3-PyH H Bu 2,6-di-Cl-Phe MeO CH₂-3-Py H H Bu 2-Cl-6-Me-Phe MeO CH₂-3-Py H HBu 2,4-di-Cl-Phe MeO CH₂-3-Py H H Bu 2-Cl-3-Py MeO CH₂-3-Py H H Bu3-Quin MeO CH₂-3-Py H H Bu 5-Quin MeO CH₂-3-Py H H Bu 6-Quin MeOCH₂-3-Py H H Bu 8-Quin

[0208] TABLE 4

A¹ A⁵ Y² Y³ R¹ L MeO Bn H H Bu 2,6-di-iPr-Phe MeO CH₂-2-Py H H Bu2,6-di-iPr-Phe MeO CH₂-4-Py H H Bu 2,6-di-iPr-Phe MeO (CH₂)₂—NMe₂ H H Bu2,6-di-iPr-Phe MeO (CH₂)₂—NiPr₂ H H Bu 2,6-di-iPr-Phe MeO (CH₂)₂-Morp HH Bu 2,6-di-iPr-Phe MeO (CH₂)₂-Pipe H H Bu 2,6-di-iPr-Phe MeO(CH₂)₂-Pyrro H H Bu 2,6-di-iPr-Phe MeO (CH₂)₂-Pipera H H Bu2,6-di-iPr-Phe MeO (CH₂)₂-Triaz H H Bu 2,6-di-iPr-Phe MeO (CH₂)₂—OH H HBu 2,6-di-iPr-Phe MeO (CH₂)₂—OAc H H Bu 2,6-di-iPr-Phe MeO (CH₂)₂—Cl H HBu 2,6-di-iPr-Phe MeO (CH₂)₂-2-Py H H Bu 2,6-di-iPr-Phe MeO (CH₂)₃-3-PyH H Bu 2,6-di-iPr-Phe MeO (CH₂)₂-4-Py H H Bu 2,6-di-iPr-Phe MeO(CH₂)₃—NMe₂ H H Bu 2,6-di-iPr-Phe MeO (CH₂)₃—NiPr₂ H H Bu 2,6-di-iPr-PheMeO (CH₂)₃-Morp H H Bu 2,6-di-iPr-Phe MeO (CH₂)₃-Pipe H H Bu2,6-di-iPr-Phe MeO (CH₂)₃-Pipera H H Bu 2,6-di-iPr-Phe MeO (CH₂)₃-PyrroH H Bu 2,6-di-iPr-Phe MeO (CH₂)₃—OH H H Bu 2,6-di-iPr-Phe MeO (CH₂)₃—OAcH H Bu 2,6-di-iPr-Phe MeO (CH₂)₃—Cl H H Bu 2,6-di-iPr-Phe MeO(CH₂)₃-Triaz H H Bu 2,6-di-iPr-Phe MeO CH₂-3-Py H H H 2,6-di-iPr-Phe MeOCH₂-3-Py H H Me 2,6-di-iPr-Phe MeO CH₂-3-Py H H Et 2,6-di-iPr-Phe MeOCH₂-3-Py H H Pr 2,6-di-iPr-Phe MeO CH₂-3-Py H H iPr 2,6-di-iPr-Phe MeOCH₂-3-Py H H 3-Butenyl 2,6-di-iPr-Phe MeO CH₂-3-Py H H 3-Butynyl2,6-di-iPr-Phe MeO CH₂-3-Py H H 4-Pentenyl 2,6-di-iPr-Phe

[0209] TABLE 5

A¹ A⁵ Y² Y³ R¹ L MeO CH₂-3-Py H H CH₂-Ph 2,6-di-iPr-Phe MeO CH₂-3-Py H HCH₂-2-Py 2,6-di-iPr-Phe MeO CH₂-3-Py H H CH₂-3-Py 2,6-di-iPr-Phe MeOCH₂-3-Py H H CH₂-4-Py 2,6-di-iPr-Phe MeO CH₂-3-Py H H CH₂CO₂H2,6-di-iPr-Phe MeO CH₂-3-Py H H CH₂CN 2,6-di-iPr-Phe MeO CH₂-3-Py H HCH₂OH 2,6-di-iPr-Phe MeO CH₂-3-Py H H CH₂OMe 2,6-di-iPr-Phe MeO CH₂-3-PyH H Bn 2,6-di-iPr-Phe MeO CH₂-3-Py H H (CH₂)₂OH 2,6-di-iPr-Phe MeOCH₂-3-Py H H (CH₂)₂CN 2,6-di-iPr-Phe MeO CH₂-3-Py H H (CH₂)₂NH₂2,6-di-iPr-Phe MeO CH₂-3-Py H H (CH₂)₂NMe₂ 2,6-di-iPr-Phe MeO CH₂-3-Py HH (CH₂)₂NHAc 2,6-di-iPr-Phe MeO CH₂-3-Py H H (CH₂)₃OH 2,6-di-iPr-Phe MeOCH₂-3-Py H H (CH₂)₃CN 2,6-di-iPr-Phe MeO CH₂-3-Py H H (CH₂)₃NH₂2,6-di-iPr-Phe MeO CH₂-3-Py H H (CH₂)₃NMe₂ 2,6-di-iPr-Phe MeO CH₂-3-Py HH (CH₂)₃NHAc 2,6-di-iPr-Phe Me CH₂-3-Py H H Bu 2,6-di-iPr-Phe BrCH₂-3-Py H H Bu 2,6-di-iPr-Phe Cl CH₂-3-Py H H Bu 2,6-di-iPr-Phe FCH₂-3-Py H H Bu 2,6-di-iPr-Phe CF₃ CH₂-3-Py H H Bu 2,6-di-iPr-Phe EtOCH₂-3-Py H H Bu 2,6-di-iPr-Phe BnO CH₂-3-Py H H Bu 2,6-di-iPr-Phe HOCH₂-3-Py H H Bu 2,6-di-iPr-Phe AcNH CH₂-3-Py H H Bu 2,6-di-iPr-Phe MeOCH₂-3-Py Me H Bu 2,6-di-iPr-Phe MeO CH₂-3-Py Me H Bu 2,6-di-F-Phe MeOCH₂-3-Py Me H Bu 2,4,6-tri-F-Phe MeO CH₂-3-Py Me H Bu 2,4,6-tri-MeO-PheMeO CH₂-2-Py Me H Bu 2,6-di-iPr-Phe

[0210] TABLE 6

A¹ A⁵ Y² Y³ R¹ L MeO CH₂-3-Py Me H Bu 2,6-di-iPr-Phe MeO (CH₂)₂-Morp MeH Bu 2,6-di-iPr-Phe MeO (CH₂)₂-Pipe Me H Bu 2,6-di-iPr-Phe MeO(CH₂)₂-Pyrro Me H Bu 2,6-di-iPr-Phe MeO (CH₂)₂-Triaz Me H Bu2,6-di-iPr-Phe MeO (CH₂)₃-Morp Me H Bu 2,6-di-iPr-Phe MeO (CH₂)₃-TriazMe H Bu 2,6-di-iPr-Phe MeO CH₂-2-Py Me H (CH₂)₂OMe 2,6-di-iPr-Phe MeOCH₂-2-Py Me H (CH₂)₃CN 2,6-di-iPr-Phe

[0211] TABLE 7

A¹ A⁵ Y² R¹ L MeO Me H Bu 2,6-bis-MeS-4-Me-Phe MeO Me H Bu2,4-bis-MeS-6-Me-3-Py MeO Me H Bu 2-tBu-5-(CH₂-Morp)-Phe MeO Me H Bu2-tBu-5-(CH₂-Pipe)-Phe MeO Me H Bu 2-tBu-5-(CH₂-Pyrro)-Phe MeO Me H Bu2-tBu-5-(CH₂-Pipera)-Phe MeO Me H Bu 2-tBu-5-(CH₂-Imd)-Phe MeO Me H Bu2-tBu-5-(CH₂-Pyrz)-Phe MeO Me H Bu 2-tBu-5-CH₂-(4-Me-Pyrz)-Phe MeO Me HBu 2-tBu-5-(CH₂—NMe₂)-Phe MeO Me H Bu 2-tBu-5-(CH₂-NEt₂)-Phe MeO Me H Bu2-tBu-5-(CH₂-NPr₂)-Phe MeO Me H Bu 2-tBu-5-(CH₂—NiPr₂)-Phe MeO Me H Bu2-tBu-5-{CH₂—NMe(—CH₂-2-Py)}-Phe MeO Me H Bu2-tBu-5-{CH₂—NMe(—CH₂-3-Py)}-Phe MeO Me H Bu2-tBu-5-{CH₂—NMe(—CH₂-4-Py)}-Phe MeO Me H Bu2-tBu-5-{CH₂-NEt(—CH₂-2-Py)}-Phe MeO Me H Bu2-tBu-5-{CH₂—NH(—CH₂-2-Py)}-Phe MeO Me H Bu 2-iPr-5-(CH₂-Imd)-Phe H Me HBu 2,6-bis-MeS-4-Me-3-Py H Me H Bu 2-tBu-5-(CH₂-Morp)-Phe H Me H Bu2-tBu-5-(CH₂-Pipe)-Phe H Me H Bu 2-tBu-5-(CH₂-Pyrro)-Phe H Me H Bu2-tBu-5-(CH₂-Imd)-Phe H Me H Bu 2-tBu-5-(CH₂-Pyrz)-Phe H Me H Bu2-tBu-5-CH₂-(4-Me-Pyrz)-Phe H Me H Bu 2-tBu-5-(CH₂—NMe₂)-Phe H Me H Bu2-tBu-5-(CH₂-NEt₂)-Phe H Me H Bu 2-tBu-5-(CH₂-NPr₂)-Phe H Me H Bu2-tBu-5-(CH₂-NiPr₂)-Phe

[0212] TABLE 8

A¹ A⁵ Y² R¹ L H Me H Bu 2-tBu-5-{CH₂—NMe(—CH₂-2-Py)}-Phe H Me H Bu2-tBu-5-{CH₂—NMe(—CH₂-3-Py)}-Phe H Me H Bu2-tBu-5-{CH₂—NMe(—CH₂-4-Py)}-Phe H Me H Bu2-tBu-5-{CH₂-NEt(—CH₂-2-Py)}-Phe H Me H Bu2-tBu-5-{CH₂—NH(—CH₂-2-Py)}-Phe H Me H Bu 2-iPr-5-(CH₂-Imd)-Phe MeOCH₂-3-Py H Bu 2,6-di-MeS-4-Me-Phe MeO CH₂-3-Py H Bu 2,6-di-MeS-6-Me-3-PyMeO CH₂-3-Py H Bu 2-tBu-5-(CH₂-Morp)-Phe MeO CH₂-3-Py H Bu2-tBu-5-(CH₂-Pipe)-Phe MeO CH₂-3-Py H Bu 2-tBu-5-(CH₂-Pyrro)-Phe MeOCH₂-3-Py H Bu 2-tBu-5-(CH₂-Pipera)-Phe MeO CH₂-3-Py H Bu2-tBu-5-(CH₂-Imd)-Phe MeO CH₂-3-Py H Bu 2-tBu-5-(CH₂-Pyrz)-Phe MeOCH₂-3-Py H Bu 2-tBu-5-CH₂-(4-Me-Pyrz)-Phe MeO CH₂-3-Py H Bu2-iPr-5-CH₂-Imd-Phe MeO Me Me Bu 2,6-di-MeS-4-Me-Phe MeO Me Me Bu2,4-di-MeS-6-Me-3-Py MeO Me Me Bu 2-tBu-5-(CH₂-Morp)-Phe MeO Me Me Bu2-tBu-5-(CH₂-Pipe)-Phe MeO Me Me Bu 2-tBu-5-(CH₂-Pyrro)-Phe MeO Me Me Bu2-tBu-5-(CH₂-Pipera)-Phe MeO Me Me Bu 2-tBu-5-(CH₂-Imd)-Phe MeO Me Me Bu2-tBu-5-(CH₂-Pyrz)-Phe MeO Me Me Bu 2-tBu-5-CH₂-(4-Me-Pyrz)-Phe MeO MeMe Bu 2-iPr-5-CH₂-Imd-Phe MeO Me Me H 2-tBu-5-(CH₂-Morp)-Phe MeO Me MeMe 2-tBu-5-(CH₂-Morp)-Phe MeO Me Me Et 2-tBu-5-(CH₂-Morp)-Phe MeO Me MePr 2-tBu-5-(CH₂-Morp)-Phe MeO Me Me iPr 2-tBu-5-(CH₂-Morp)-Phe

[0213] TABLE 9

A¹ R⁶ R⁷ R¹⁶ R¹⁷ R¹ Y² L MeO H H H H Bu H 2,6-di-iPr-Phe MeO H H H Me BuH 2,6-di-iPr-Phe MeO H H H Et Bu H 2,6-di-iPr-Phe MeO H H H iPr Bu H2,6-di-iPr-Phe MeO H H H Hex Bu H 2,6-di-iPr-Phe MeO H H H cHex Bu H2,6-di-iPr-Phe MeO H H H CH₂NEt₂ Bu H 2,6-di-iPr-Phe MeO H H H(CH₂)₂NEt₂ Bu H 2,6-di-iPr-Phe MeO H H Me Me Bu H 2,6-di-iPr-Phe MeO H HEt Et Bu H 2,6-di-iPr-Phe MeO H H Et Et Bu Me 2,6-di-iPr-Phe MeO H H iPriPr Bu H 2,6-di-iPr-Phe MeO H H Hex Hex Bu H 2,6-di-iPr-Phe MeO H H MeBn Bu H 2,6-di-iPr-Phe MeO H H Et Bn Bu H 2,6-di-iPr-Phe MeO H H HCH₂-2-Py Bu H 2,6-di-iPr-Phe MeO H H H CH₂-3-Py Bu H 2,6-di-iPr-Phe MeOH H H CH₂-4-Py Bu H 2,6-di-iPr-Phe MeO H H Me CH₂-2-Py Bu H2,6-di-iPr-Phe MeO H H Me CH₂-3-Py Bu H 2,6-di-iPr-Phe MeO H H MeCH₂-4-Py Bu H 2,6-di-iPr-Phe MeO H H Me CH₂-4-Py Bu Me 2,6-di-iPr-PheMeO H H (CH₂)₄ Bu H 2,6-di-iPr-Phe MeO H H (CH₂)₅ Bu H 2,6-di-iPr-PheMeO H H (CH₂)₆ Bu H 2,6-di-iPr-Phe MeO H H (CH₂)₄—O—(CH₂)₂ Bu H2,6-di-iPr-Phe

[0214] TABLE 10

A¹ R⁶ R⁷ R¹⁶ R¹⁷ R¹ Y² L MeO H H Et Et Bu H 2-iPr-Phe MeO H H Et Et Bu H2,4,6-tri-Me-Phe MeO H H Et Et Bu H 2,6-di-F-Phe MeO H H Et Et Bu H2,4,6-tri-F-Phe MeO H H Et Et Bu H 2-Me-6-tBu-Phe MeO H H Et Et Bu H2,4,6-tri-MeO-Phe MeO H H Et Et Bu H 2,6-bis-MeS-4-Me-Phe MeO H H Et EtBu H 2-tBu-5-(CH₂-Imd)-Phe MeO H H Et Et Bu H 2-tBu-5-(CH₂-Pyrz)-Phe MeOH H Et Et Bu H 2-iPr-5-(CH₂-Imd)-Phe EtO H H Et Et Bu H 2-iPr-Phe EtO HH Et Et Bu H 2,6-di-iPr-Phe EtO H H Et Et Bu H 2,4,6-tri-Me-Phe EtO H HEt Et Bu H 2,6-di-F-Phe EtO H H Et Et Bu H 2,4,6-tri-F-Phe EtO H H Et EtBu H 2-Me-6-tBu-Phe EtO H H Et Et Bu H 2,4,6-tri-MeO-Phe EtO H H Et EtBu H 2,6-bis-MeS-4-Me-Phe EtO H H Et Et Bu H 2-tBu-5-(CH₂-Imd)-Phe HO HH Et Et Bu H 2-iPr-Phe HO H H Et Et Bu H 2,6-di-iPr-Phe HO H H Et Et BuH 2,4,6-tri-Me-Phe HO H H Et Et Bu H 2,6-di-F-Phe HO H H Et Et Bu H2,4,6-tri-F-Phe HO H H Et Et Bu H 2-Me-6-tBu-Phe HO H H Et Et Bu H2,4,6-tri-MeO-Phe HO H H Et Et Bu H 2,6-bis-MeS-4-Me-Phe HO H H Et Et BuH 2-tBu-5-(CH₂-Imd)-Phe F H H Et Et Bu H 2-iPr-Phe F H H Et Et Bu H2,6-di-iPr-Phe F H H Et Et Bu H 2,4,6-tri-Me-Phe

[0215] TABLE 11

A¹ R⁶ R⁷ R¹⁶ R¹⁷ R¹ Y² L F H H Et Et Bu H 2,6-di-F-Phe F H H Et Et Bu H2,4,6-tri-F-Phe F H H Et Et Bu H 2-Me-6-tBu-Phe F H H Et Et Bu H2,4,6-tri-MeO-Phe F H H Et Et Bu H 2,6-bis-MeS-4-Me-Phe F H H Et Et Bu H2-tBu-5-(CH₂-Imd)-Phe MeO Me Me Et Et Bu H 2,6-di-iPr-Phe MeO Et Et EtEt Bu H 2,6-di-iPr-Phe MeO H H Et Et Me H 2,6-di-iPr-Phe MeO H H Et EtEt H 2,6-di-iPr-Phe MeO H H Et Et Pr H 2,6-di-iPr-Phe MeO H H Et Et iPrH 2,6-di-iPr-Phe

[0216] TABLE 12

Y¹ Y² Y³ R¹ L Me H H Bu C(CH₃)₂(CH₂)₉CH₃ Et H H Bu C(CH₃)₂(CH₂)₉CH₃ Pr HH Bu C(CH₃)₂(CH₂)₉CH₃ iPr H H Bu C(CH₃)₂(CH₂)₉CH₃ Bu H H BuC(CH₃)₂(CH₂)₉CH₃ (CH₂)₉CH₃ H H Bu C(CH₃)₂(CH2)₉CH₃ (CH₂)₁₀CH₃ H H BuC(CH₃)₂(CH₂)₉CH₃ (CH₂)₁₄CH₃ H H Bu C(CH₃)₂(CH₂)₉CH₃ Ph H H BuC(CH₃)₂(CH₂)₉CH₃ 2-Py H H Bu C(CH₃)₂(CH₂)₉CH₃ 3-Py H H BuC(CH₃)₂(CH₂)₉CH₃ 4-Py H H Bu C(CH₃)₂(CH₂)₉CH₃ H Ph H Bu C(CH₃)₂(CH₂)₉CH₃H H Ph Bu C(CH₃)₂(CH₂)₉CH₃ H H Ph H C(CH₃)₂(CH₂)₉CH₃ H H Ph MeC(CH₃)₂(CH₂)₉CH₃ H H Ph Et C(CH₃)₂(CH₂)₉CH₃ H H Ph Pr C(CH₃)₂(CH₂)₉CH₃ HH Ph iPr C(CH₃)₂(CH₂)₉CH₃ 3-MeO—Ph H H H C(CH₃)₂(CH₂)₉CH₃ 3-MeO—Ph H HMe C(CH₃)₂(CH₂)₉CH₃ 3-MeO—Ph H H Et C(CH₃)₂(CH₂)₉CH₃ 3-MeO—Ph H H PrC(CH₃)₂(CH₂)₉CH₃ 3-MeO—Ph H H iPr C(CH₃)₂(CH₂)₉CH₃ 3-MeO—Ph H H BuC(CH₃)₂(CH₂)₉CH₃ 3-MeO—Ph H H Bu (CH₂)₃CH₃ 3-MeO—Ph H H Bu (CH₂)₉CH₃3-MeO—Ph H H Bu (CH₂)₁₉CH₃ 3-MeO—Ph H H Bu Ph

EXAMPLES

[0217] The present invention is illustrated by Examples, but should notbe construed to be limited thereto.

Example 1

[0218] Preparation ofN-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0219] To a suspension of1-butyl-3-carbamoyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine(10.0 g, 27.2 mmol) in N,N-dimethylformamide (100 ml) was added leadtetracetate (14.5 g, 32.6 mmol), and the mixture was stirred at roomtemperature for 0.5 hour. Subsequently, to the mixture was added2,6-diisopropylaniline (5.3 g, 30 mmol) at the same temperature, and themixture was stirred at 40° C. for 50° C. for 1.5 hour. After allowed tocool, ethyl acetate (500 ml) was added to the mixture, and the mixturewas filtered through a celite pad. The filtrate was washed successivelywith water, 4 N aqueous hydrochloric acid solution, water and asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated under reduced pressure to the volume of about100 ml. The resultant was stirred for 2 hours under cooling withice-water, and the compound (9.81 g, 18.6 mmol, 68%) as colorlesscrystals.

[0220] M.p. 179-182° C.

Example 2

[0221] Preparation ofN-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0222] To a 1 N aqueuos sodium hydroxide solution (48 ml, 48 mmol) wasadded dropwise bromine (1.2 ml, 24 mmol) under ice-cooling, and themixture was stirred for 30 minutes. The pale yellow solution thusobtained was added dropwise to a suspension of1-butyl-3-carbamoyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine(2.1 g, 6 mmol) and tetrabutylammonium hydrogen sulfate (102 mg, 0.3mmol) in toluene (210 ml) at room temperature, and the mixture wasstirred at the same temperature for 4 hours. To the mixture was added asolution of acetic acid (35 ml) and 2,6-diisopropylaniline (1.6 g, 9.0mmol) in toluene (35 ml) at room temperature, and the mixture wasstirred at the same temperature for 1.5 hour. Water was added to thereaction solution, and the mixture was extracted with ethyl acetate,washed with water, washed with a saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate. The residue wasconcentrated under reduced pressure, and purified by silica gel columnchromatography (ethyl acetate/hexane={fraction (1/10)} to ½) to give thetitle compound (2.34 g, 4.44 mmol, 74%) as a colorless solid.

[0223] M.p. 178-181° C.

Example 3

[0224] Preparation of1-butyl-3-amino-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine;

[0225] To a 1 N aqueous sodium hydroxide-solution (88 ml, 88 mmol) wasadded dropwise bromine (1.0 ml, 19.4 mmol) under ice-cooling, and themixture was stirred for 30 minutes. The pale yellow solution thusobtained was added dropwise to a suspension of1-butyl-3-carbamoyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine (5.0 g, 14.2 ml) and tetrabutylammonium hydrogensulfate (250 mg. 0.71 mmol) in tetrahydrofuran (500 ml) at roomtemperature, and the mixture was stirred at the same temperature for 6.5hours. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate, washed with water, washed with a saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. To the concentratedresidue was added 2-propanol (40 ml), and the mixture was stirred for 3hours under ice-cooling. The precipitated solid was collected byfiltration to give the title compound (3.49 g, 10.8 mmol, 76%) as paleyellow powder.

[0226] M.p. 138-141° C.

Example 4

[0227] Preparation ofN-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0228] To a solution of3-amino-1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine(1.70 g, 5.26 mmol) in tetrahydrofuran (14 ml) was added phenylchlorocarbonate (1.32 ml, 10.5 ml), and the mixture was stirred at40-50° C. for 3 hours. The mixture was allowed to cool, and thereto wasadded water, and the mixture was extracted with water. The extract waswashed with a 5% aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was dissolved in dimethylformamide (10 ml), andthereto was added a solution of 2,6-diisopropylaniline (1.24 g, 6.31mmol) and dimethylformamide (5 ml) and 4-dimethylaminopyridine (0.62 g,5.26 mmol), and the mixture was stirred at room temperature for onehour. To the reaction solution was added water, and the mixture wasextracted with ethyl acetate. The extract was washed successively with a5% aqueous sodium hydrogen carbonate solution and a 5% aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was crystallized fromethyl acetate to give the title compound (1.75 g, 3.32 mmol) ascolorless crystals.

[0229] M.p. 179-182° C.

Example 5

[0230] Preparation of1-butyl-3-phthalimide-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine:

[0231] To a solution of1-{(N-butyl-N-phthalimidacetyl)amino}-3-(3-methoxybenzoyl)pyridine (3.44g, 7.30 mmol) in N,N-dimethylformamide (18 ml) was added potassiumcarbonate (6.05 g, 43.8 mmol), and the mixture was stirred at 90-100° C.for 3 hours. The mixture was cooled to room temperature, and water wasadded thereto, and the mixture was extracted with ethyl acetate. Theextract was washed successively with a 5% aqueous sodium hydrogencarbonate solution and a 5% aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure togive the title compound (2.15 g, 4.74 mmol, 65%) as brown crystals,which were used in the subsequent reaction without further purification.

[0232]¹H NMR δ (CDCl₃) 0.91 (3 H, t, J=7.3 Hz), 1.38-1.45 (2 H, m),1.68-1.79 (2 H, m), 3.66 (3 H, s), 4.52 (2 H, t, J=7.3 Hz), 6.81-6.88 (3H, m), 7.07 (1 H, dd, J=8.1 Hz, 4.81 Hz), 7.22 (1 H, ddd, J=7.5 Hz, 7.5Hz, 3.3 Hz), 7.58-7.63 (3 H, m), 7.70-7.76 (2 H, m), 8.60 (1 H, dd,J=4.8 Hz, 1.7 Hz)

Example 6

[0233] Preparation of1-butyl-3-amino-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine:

[0234] To a solution of1-butyl-3-phthalimide-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine(2.15 g, 4.74 mmol) in ethanol (16 ml) was added a 30% solution ofmethylamine in ethanol (4 ml), and the mixture was stirred at roomtemperature for 5 hours. The mixture was concentrated under reducedpressure, and the residue was dissolved in ethyl acetate. The mixturewas washed successively with a 5% aqueous sodium hydrogen carbonatesolution and a 5% aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate/hexane={fraction (1/10)} to ¼) to give the title compound (0.78g, 2.43 mmol, 51%) as colorless crystals.

[0235]¹H NMR δ (CDCl₃) 1.01 (3 H, t, J=7.3 Hz), 1.44-1.54 (2 H, m),1.76-1.86 (2 H, m), 3.84 (3 H, s), 4.49 (2 H, brs), 4.66 (2 H, t, J=7.5Hz), 6.87-7.04 (4 H, m), 7.42-7.50 (2 H, m), 8.35 (1 H, dd, J=4.6 Hz,1.8 Hz)

Example 7

[0236] Preparation of1-butyl-3-amino-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine:

[0237] To a suspension of N-phthaloylglycine (4.76 g, 23.2 mmol) intoluene (24 ml) were added thionyl chloride (5.08 ml, 69.6 mmol) anddimethylformamide (0.4 ml), and the mixture was stirred at 50-60° C. for30 minutes, cooled, and concentrated under reduced pressure to removethe solvent. To the resulting solid was added toluene (12 ml), andfurther thereto were added a solution of2-(butylamino)-3-(3-methoxybenzoyl)pyridine (3.30 g, 11.6 mmol) intoluene (15 ml) and pyridine (27 ml), and the mixture was stirred at80-90° C. for 2 hours. After allowed to cool, to the mixture were addedpotassium carbonate (9.62 g, 69.6 mmol) and N,N-dimethylformamide (54ml), and the mixture was further stirred at 90- 100° C. for 8 hours.After allowed to cool, a 40% aqueous methylamine solution (4.99 ml, 58.0mmol) was added, and the mixture was stirred at room temperature for onehour. Water was added to the reaction solution, and the mixture wasextracted with toluene. The extract was washed successively with 1 Nhydrochloric acid, water, a 5% aqueous sodium hydrogen carbonatesolution and a 5% aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Theresulting solid was recrytallized from 2-propanol to give the titlecompound (2.30 g, 7.11 mmol, 61%) as colorless prisms.

[0238] M.p. 140- 142° C.

Example 8

[0239] Preparation ofN-{1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihydro-pyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea:

[0240] To a solution of1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihydropyridine-3-carboxylic acid(4.61 g, 15.3 mmol) in DMF (dimethyformamide; 50 ml) were added DPPA(diphenylphosphoryl azide; 5.06 g, 18.4 mmol) and triethylamine (2.7ml), and the mixture was stirred at about 50° C. for one hour. To themixture was added 2,6-diisopropylaniline (3.26 g, 18.4 mmol), and themixture was stirred at about 70° C. for 4.5 hours. To the reactionsolution was added water, and the mixture was extracted with ethylacetate, washed with a saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate. The solvent was distilled off,and the resulting residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:1) to give the title compound(6.51 g, yield; 90%) as to white crystals.

[0241] M.p. 176-178° C.

[0242] IR (KBr) 3324, 3068, 1703, 1643, 1565 cm⁻¹

Example 9

[0243] Preparation ofN-{1-butyl-2-oxo-4-(3-hydroxy)phenyl-1,2-dihydro-pyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea:

[0244] To a solution ofN-{1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihydropyridin-3-y}-N′-(2,6-dihydropropylphenyl)urea(3.84 g, 8.07 mmol) in methylene chloride (100 ml) was added BBr₃ borontribromide; 3.1 ml, 32.3 mmol), and the mixture was stirred at roomtemperature for 2 hours. Water was added to the reaction solution, andbasified with a saturated aqueous sodium hydrogen carbonate solution.The mixture was extracted with ethyl acetate, washed with a saturatedaqueous sodium chloride solution, and dried over magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the resultingcrystals were collected by filtration to give the title compound (3.61g, yield; 97%) as white crystals.

[0245] M.p. 188-191° C.

Example 10

[0246] Preparation ofN-[1-butyl-2-oxo-4-[3-{3-(1,2,4-triazol-1-yl)propoxy}-phenyl]-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0247] To a solution ofN-{1-butyl-2-oxo-4-(3-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea(500 mg, 1.08 mmol) in DMF (5 ml) were added potassium carbonate (4.48g, 32.4 mmol), 1-(3-bromopropyl)-1,2,4-triazole (247 mg, 1.30 mmol), andsodium iodide (81 mg, 0.54 mmol), and the mixture was stirred at about50° C. for 9 hours. Potassium carbonate was removed by filtration, andwater was added to the filtrate, and extracted with ethyl acetate. Theextract was washed with a saturated aqueous sodium chloride solution,and dried over magnesium sulfate. The solvent was evaporated underreduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (ethyl acetate) to give the title compound (420mg, yield; 68%) as pale yellow amorphous.

[0248]¹H NMR δ (DMSO-d₆) 0.94 (t, J=7.21 Hz, 3 H), 1.00 (bs, 12 H),1.28-1.41 (m, 2 H), 1.63-1.71 (m, 2 H), 2.15-2.26 (m, 2 H), 2.88-2.91(m, 2 H), 3.94-3.99 (m, 4 H), 4.35 (t, J=7.0 Hz, 2 H), 6.23 (d, J=7.2Hz, 1 H), 6.86 (d J=7.9 H, 1 H), 6.99-7.07 (m, 4 H), 7.13 (dd, J=7.9,7.9 Hz, 1 H), 7.26 (dd, J=7.9, 7.9 Hz, 1 H), 7.54 (d, J=7.2 Hz, 1 H),7.77 (s, 1 H), 7.81 (s, 1 H), 7.96 (s, 1 H), 8.52 (s, 1 H)

[0249] IR (KBr) 3321, 1706, 1645, 1584 cm⁻¹

[0250] Preparation of the hydrochloride thereof:

[0251] To a solution ofN-[1-butyl-2-oxo-4-[3-{3-(1,2,4-triazol-1-yl)-propoxy}phenyl]-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea (330 mg, 0.578mmol) in THF (tetrahydrofuran; 5 ml) was added 1 N solution ofhydrochoric acid in ether (1.7 ml), and the mixture was stirred. Thesolvent was evaporated under reduced pressure, and to the residue wasadded ether. The precipitated crystals were collected by filtration, anddried to give the hydrochloride of the title compound (305 mg, 87%) aspale yellow crystals.

[0252] M.p. 90-95° C.

[0253] IR (KBr) 3262, 1645, 1600 cm⁻¹

Example 11

[0254] Preparation ofN-[1-butyl-2-oxo-4-{(3-(3-pyridylmethoxy)phenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea

[0255] The title compound was obtained in the same manner as in Example10 fromN-{1-butyl-2-oxo-4-(3-hydroxy)phenyl)-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)ureaand 3-chloromethylpyridine hydrochloride.

[0256]¹H NMR δ (CD₃OD) 0.99 (t, J=7.3 Hz, 3 H), 1.05 (bs, 12 H),1.39-1.44 (m, 2 H), 1.75-1.78 (m, 2 H), 2.99 (m, 2 H), 4.05 (t, J=7.50Hz, 2 H), 5.18 (s, 2 H), 6.37 (d, J=7.0 Hz, 1 H), 7.04-7.06 (m, 3 H),7.14-7.21 (m, 3 H), 7.36 (dd, J=7.9, 7.9 Hz, 1 H), 7.44-7.52 (m, 2 H),7.76 (d, J=7.0 Hz, 1 H), 8.50 (d, J=4.8 Hz, 1 H), 8.64 (s, 1 H)

[0257] The hydrochloride of the title compound was obtained in the samemanner as in Example 10.

[0258] M.p. 98-100° C.

[0259] IR (KBr) 3152, 1646, 1583 cm⁻¹

Example 12

[0260] Preparation ofN-[1-butyl-2-oxo-4-[3-(2-diethylaminoethoxy)phenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea

[0261] The title compound was obtained in the same manner as in Example10 fromN-{1-butyl-2-oxo-4-(3-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)ureaand N,N-diethylaminoethyl chloride hydrochloride.

[0262]¹H NMR 67 (DMSO-d₆) 0.91-1.06 (m, 21 H), 1.29-1.38 (m, 2 H),1.63-1.71 (m, 2 H), 2.57 (bs, 2 H), 2.81 (bs, 2 H), 2.88-2.97 (m, 2 H),2.88-2.91 (m, 2 H), 3.94-4.03 (m, 6 H), 6.23 (d, J=7.2 Hz, 1 H), 6.87(d, J=8.1 Hz, 1 H), 7.00-7.03 (m, 4 H), 7.13 (dd, J=7.7, 7.7 Hz, 1 H),7.26 (dd, J=8.1, 8.1 H, I1 H), 7.53 (d, J=7.2 Hz, 1 H), 7.77 (s, 1 H),7.82 (s, 1 H)

[0263] The hydrochloride of the title compound was obtained in the samemanner as in Example 10.

[0264] M.p. 125-130° C.

[0265] IR (KBr) 3272, 1692, 1646, 1601 cm⁻¹

Example 13

[0266] Preparation ofN-{1-butyl-2-oxo-4-(3-bromo)phenyl-1,2-dihydropyridin-3-yl)-N′-(2,6-diisopropylphenyl)urea

[0267] The title compound was obtained in the same manner as in Example8 from 1-butyl-2-oxo-4-(3-bromo)phenyl-1,2-dihydropyridin-3-carboxylicacid and 2,6-diisopropylaniline.

[0268] M.p. 169-172° C.

[0269] IR (KBr) 3314, 1710, 1645, 1586 cm⁻¹

Example 14

[0270] Preparation ofN-[1-butyl-2-oxo-4-[3-{3-(diethylamino)-1-propynyl}-phenyl]-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0271] To a solution ofN-{1-butyl-2-oxo-4-(3-bromo)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea(1.23 g, 2.35 mmol) in DMF (6 ml) were added N,N-diethylpropargylamine(784 mg), triphenylphosphine (100 mg, 0.376 mmol), copper iodide (36 mg,0.188 mmol), triethylamine (2.0 ml), and 10% palladium on active carbon(100 mg, 0.094 mmol), and the mixture was stirred at about 80° C. for 13hours. The mixture was filtered through a cerite pad, and the filtratewas diluted with ethyl acetate, washed with a saturated aqueous sodiumchloride solution and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (chloroform:methanol=30:1) to give thetitle compound (813 mg, yield; 62%).

[0272] M.p. 76-82° C.

[0273] IR (KBr) 3323, 1709, 1645, 1584 cm⁻¹

[0274] Preparation of the hydrochloride thereof:

[0275] To a solution ofN-[1-butyl-2-oxo-4-[3-{3-(diethylamino)-1-propynyl}phenyl]-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)-urea(393 mg, 0.707 mmol) in THF (5 ml) was added 1 N solution of hydrochoricacid in ether (2.1 ml), and the mixture was stirred. The solvent wasevaporated under reduced pressure, and to the residue was added hexane.The precipitated crystals were collected by filtration, and dried togive the hydrochloride of the title compound (414 mg, yield; 99%) asbrown crystals.

[0276]¹H NMR δ (CD₃OD) 0.99 (t, J=7.5 Hz, 3 H), 1.06 (bd, 12 H), 1.38(t, J=7.2 Hz, 6 H), 1.38-1.46 (m, 2 H), 1.73-1.83 (m, 2 H), 2.84-2.93(m, 2 H), 3.37 (q, J=7.2 Hz, 4 H), 4.06 (t, J=7.5 Hz, 2 H), 4.36 (s, 2H), 6.34 (d, J=7.0 Hz, 1 H), 7.05 (d, J=7.3 Hz, 2 H), 7.16 (dd, J=6.8,6.8 Hz, 1 H), 7.45 (dd, J=7.5, 7.5 Hz, 1 H), 7.52-7.65 (m, 4 H)

Example 15

[0277] Preparation ofN-{1-butyl-2-oxo-4-(3-bromo)phenyl-5-methyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea:

[0278] The title compound was obtained in the same manner as in Example8 from1-butyl-2-oxo-4-(3-bromo)phenyl-5-methyl-1,2-dihydropyridin-3-carboxylicacid and 2,6-diisopropylaniline.

[0279] M.p. 199-200° C.

[0280] IR (KBr) 3315, 3266, 3226, 1719, 1650, 1575 cm⁻¹

Example 16

[0281] Preparation ofN-[1-butyl-2-oxo-4-[3-{3-(diethylamino)-1-propynyl}-phenyl]-5-methyl-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0282] The title compound was obtained in the same manner as in Example14 fromN-{1-butyl-2-oxo-4-(3-bromo)phenyl-5-methyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)ureaand N,N-diethylpropargylamine.

[0283]¹H NMR δ (CD₃OD) 0.99 (t, J=7.3 Hz, 6 H), 1.07-1.15 (m, 15 H),1.35-1.47 (m, 2 H), 1.73-1.80 (m, 2 H), 1.84 (s, 3 H), 2.67 ((q, J=7.3Hz, 4 H), 2.83 (bs, 2 H), 3.67 (s, 2 H), 4.03 (t, J=7.3 Hz, 2 H), 7.05(d, J=7.3 Hz, 2 H), 7.16 (dd, J=7.3, 7.3 Hz, 1 H), 7.24-7.31 (m, 2 H),7.38-7.46 (m, 3 H)

[0284] The hydrochloride of the title compound was obtained in the samemanner as in Example 10.

[0285] M.p. 159-162° C.

[0286] IR (KBr) 3320, 2236, 1654, 1574 cm⁻¹

Example 17

[0287] Preparation ofN-{1-butyl-2-oxo-4-(5-bromo-2-methoxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea:

[0288] The title compound was obtained in the same manner as in Example8 from1-butyl-2-oxo-4-(5-bromo-2-methoxy)phenyl-1,2-dihydropyridin-3-carboxylicacid and 2,6-diisopropylaniline.

[0289] M.p. 179-181° C.

[0290] IR (KBr) 3322, 1671, 1645, 1584 cm⁻¹

[0291] Example 18

[0292] Preparation ofN-[1-butyl-2-oxo-4-[5-{3-(diethylamino)-1-propynyl}-2-methoxy]phenyl-5-methyl-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0293] The title compound was obtained in the same manner as in Example14 fromN-{1-butyl-2-oxo-4-(5-bromo-2-methoxy)phenyl-5-methyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)ureaand N,N-diethylpropargylamine.

[0294]¹H NMR δ (CD₃OD) 0.96 (t, J=7.3 Hz, 3 H), 0.98-1.13 (m, 18 H),1.33-1.46 (m, 2 H), 1.69-1.79 (m, 2 H), 2.66 (q, J=7.2 Hz, 4 H),2.81-2.90 (m, 2 H), 2.81-2.90 (m, 2 H), 3.64 (s, 2 H), 3.82 (s, 3 H),4.01 (t, J=7.2 Hz, 2 H), 6.27 (d, J=7.2 Hz, 1 H), 7.02-7.05 (m, 3 H),7.14 (dd, J=7.0, 7.0 Hz, 1 H), 7.33 (d, J=1.8 Hz, 1 H), 7.42-7.45 (m, 2H)

[0295] The hydrochloride of the title compound was obtained in the samemanner as in Example 10.

[0296] M.p. 208-210° C.

[0297] IR (KBr) 3437, 2232, 1646, 1599 cm⁻¹

Example 19

[0298] Preparation ofN-{1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea:

[0299] The title compound was obtained in the same manner as in Example8 from1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydropyridin-3-carboxylicacid and 2,6-diisopropylaniline.

[0300] M.p. 165-167° C.

Example 20

[0301] Preparation ofN-{1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydropyridin-3yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3yl}urea:

[0302] The title compound was obtained in the same manner as in Example8 from1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydropyridin-3-carboxylicacid and 3-amino-2,4-bis(methylthio)-6-methylpyridine.

[0303] M.p. 193-197° C. (decomposed)

[0304]¹H NMR δ (DMSO-d₆) 0.94 (t, J=7.5 Hz, 3 H), 1.34 (tq, J=7.5, 7.5Hz, 2 H), 1.67 (tt, J=7.5, 7.5 Hz, 2 H), 2.30 (s, 3 H), 2.39 (s, 3 H),3.68 (s, 6 H), 3.93 (t, J=7.5 Hz, 2 H), 6.13 (d, J=7.2 Hz, 1 H),6.76-6.83 (m, 3 H), 6.92 (d, J=8.8 Hz, 1 H), 7.45 (d, J=7.2 Hz, 1 H),7.70 (bs, 1 H), 7.90 (bs, 1 H)

Example 21

[0305] Preparation ofN-{1-butyl-2-oxo-4-(2-methoxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea:

[0306] The title compound was obtained in the same manner as in Example8 from1-butyl-2-oxo-4-(2-methoxy-5-bromo)phenyl-1,2-dihydropyridin-3-carboxylicacid and 3-amino-2,4-bis(methylthio)-6-methylpyridine.

[0307]¹H NMR δ (DMSO-d₆) 0.94 (t, J=7.2 Hz, 3 H), 1.33-1.35 (m, 2 H),1.67 (m, 2 H), 2.32 (s, 6 H), 2.39 (s, 3 H), 3.72 (s, 3 H), 3.94 (bs, 2H), 6.11 (d, J=6.8 Hz, 1 H), 6.76 (s, 1 H), 6.96 (d, J=6.8 Hz, 1 H),7.24 (s, 1 H), 7.38 (d, J=8.8 Hz, 1 H), 7.43 (d, J=8.8 Hz, 1 H), 7.87(s, 1 H), 8.00 (s, 1 H)

Example 22

[0308] Preparation ofN-{1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2-tert-butyl-5-morpholinomethylphenyl)urea:

[0309] The title compound was obtained in the same manner as in Example8 from1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydropyridin-3-carboxylicacid and 2-tert-butyl-5-morpholinomethylaniline.

[0310]¹H NMR δ (DMSO-d₆) 0.94 (t, J=7.2 Hz, 3 H), 1.21 (s, 9 H), 1.36(tq, J=7.2, 7.2 Hz, 2 H), 1.69 (tt, J=7.2, 7.2 Hz, 2 H), 2.30 (bs,4 H),3.30 (s, 2 H), 3.54 (bs, 4 H), 3.66 (s, 6 H), 3.94 (t, J=7.2 Hz, 2 H),6.15 (d, J=7.2 Hz, 1 H), 6.77 (d, J=3.1 Hz, 1 H), 6.82 (dd, J=3.1, 8.3Hz, 1 H), 6.88 (s, 1 H), 6.94 (d, J=9.0 Hz, 1 H), 6.97 (d, J=9.0 Hz, 1H), 7.48 (d, J=7.2 Hz, 1 H), 7.59 (s, 1 H), 7.84 (s, 1 H)

[0311] The hydrochloride of the title compound was obtained in the samemanner as in Example 10.

[0312] M.p. 157-162° C. (decomposed)

Example 23

[0313] Preparation ofN-{1-butyl-2-oxo-4-(2-methoxy-5-benzyloxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea:

[0314] The title compound was obtained in the same manner as in Example8 from1-butyl-2-oxo-4-(2-methoxy-5-benzyloxy)phenyl-1,2-dihydropyridin-3-carboxylicacid and 2,6-diisopropylaniline.

[0315]¹H NMR δ (DMSO-d₆) 0.94 (t, J=7.3 Hz; 3 H), 1.35 (tq, J=7.3, 7.3Hz, 2 H), 1.66-1.68 (m, 2 H), 2.83-2.89 (m, 2 H), 3.69 (s, 3 H), 3.94(t, J=7.3 Hz, 2 H), 4.99 (s, 2 H), 6.13 (d, J=7.2 Hz, 1 H), 6.88 (s, 1H), 6.91-6.95 (m, 2 H), 7.01 (d, J=7.7 Hz, 2 H), 7.13 (dd, J=7.7, 7.7Hz, 1 H), 7.31-7.46 (m, 6 H), 7.69 (s, 1 H), 7.82 (s, 1 H)

Example 24

[0316] Preparation ofN-{1-butyl-2-oxo-4-(2-hydroxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea:

[0317] To a solution ofN-{1-butyl-2-oxo-4-(2-methoxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea(1.00 g, 1.80 mmol) in methylene chloride (10 ml) was added BBr₃ (0.51ml, 5.40 mmol) under ice-cooling, and the mixture was stirred underreflux for 3 hours. The reaction solution was poured into ice-water, andthe mixture was extracted with chloroform. The extract was washed with asaturated aqueous sodium chloride solution, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure, and to theresidue was added ethyl acetate. The precipitated crystals werecollected by filtration, and dried to give the title compound (662 mg,64%) as colorless crystals.

[0318] M.p. 163-165° C.

[0319] IR (KBr) 3302, 2963, 1691, 1645, 1577, 1548 cm⁻¹

Example 25

[0320] Preparation ofN-[1-butyl-2-oxo-4-[2-hydroxy-5-{3-(diethylamino)-1-propynyl}phenyl]-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)-urea:

[0321] To a solution of propylene oxide (0.07 ml, 1.04 mmol) inmethylene chloride (10 ml) was added BBr₃ (0.29 ml, 3.11 mmol) underice-cooling, and the mixture was stirred for 30 minutes. To the mixturewas addedN-[1-butyl-2-oxo-4-[2-methoxy-5-{3-(diethylamino)-1-propynyl}phenyl]-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)-urea (303 mg, 0.518 mmol), and the mixture was stirred under reflux for4 hours. To the reaction solution was added a 10% aqueous sodiumhydroxide solution, and the mixture was acidified with 3 N hydrochloricacid. The mixture was extracted with chloroform, and the extract waswashed with a saturated aqueous sodium chloride solution, and dried overmagnesium sulfate. The solvent was evaporated under reduced pressure,and the resulting residue was purified by silica gel columnchromatography (ethyl acetate: hexane=1:30) to give the title compound(77 mg, <26%) as colorless crystals.

[0322] The hydrochloride of the title compound was obtained in the samemanner as in Example 10.

[0323] M.p. 184-185° C.

[0324] IR (KBr) 3240, 2963, 2231, 1698, 1645, 1571 cm⁻¹

Example 26

[0325] Preparation ofN-{1-butyl-2-oxo-4-(2-methoxy-5-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea:

[0326] Pentamethylbenzene (815 mg, 5.50 mmol) was dissolved in TFA (11ml), and thereto was addedN-{1-butyl-2-oxo-4-(2-methoxy-5-benzyloxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)-urea(320 mg, 0.550 mmol) under ice-cooling, and the mixture was stirred at.50° C. for 3 hours. To the reaction solution were added ether and water,and the mixture was stirred under ice-cooling. The precipitated crystalswere collected by filtration, and dried to give the title compound (270mg, 100%) as colorless crystals.

[0327] M.p. 208-210° C.

[0328] IR (KBr) 3357, 3152, 2965, 1688, 1644, 1581 cm⁻¹

Example 27

[0329] Preparation ofN-[1-butyl-2-oxo-4-{2-methoxy-5-(3-pyridylmethoxy)}-phenyl-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0330] The title compound was obtained in the same manner as in Example10 fromN-[1-butyl-2-oxo-4-(2-methoxy-5-hydroxy)phenyl-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)ureaand 3-chloromethylpyridine hydrochloride.

[0331] The hydrochloride of the title compound was obtained in the samemanner as in Example 10.

[0332]¹H NMR δ (CD₃OD) 1.00 (t, J=7.3 Hz, 3 H), 1.06 (d, J=4.4 Hz, 12H), 1.41-1.48 (m, 2 H), 1.75-1.85 (m, 2 H), 2.89 (bs, 2 H), 3.82 (s, 3H), 4.07 (t, J=6.6 Hz, 2 H), 5.32 (s, 2 H), 6.32 (d, J=6.8 Hz, 1 H),7.03-7.07 (m, 5 H), 7.18 (dd, J=8.1, 8.1 Hz, 1 H), 7.54 (d, J=6.6 Hz, 1H), 8.00 (dd, J=6.8, 6.8 Hz, 1 H), 8.68 (d, J=8.1 Hz, 1 H), 8.76 (d,J=6.8 Hz, 1 H), 8.94 (s, 1 H)

Example 28

[0333] Preparation ofN-[1-butyl-2-oxo-4-(2-isopropoxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0334] The title compound was obtained in the same manner as in Example10 fromN-[1-butyl-2-oxo-4-(2-hydroxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)ureaand isopropyl iodide.

[0335]¹H NMR δ (DMSO-d₆) 0.94 (t, J=7.3 Hz, 3 H), 1.05 (bs, 12 H), 1.19(d, J=5.9 Hz, 6 H), 1.31-1.38 (m, 2 H), 1.65-1.72 (m, 2 H), 2.81-2.91(m, 2 H), 3.96 (m, 2 H), 4.55 (m, 1 H), 6.16 (d, J=7.2 Hz, 1 H), 6.98(d. J=8.4 Hz, 1 H), 7.02 (d, J=7.3 Hz, 2 H), 7.14 (dd, J=7.3, 7.3 Hz, 1H), 7.33 (d, J=2.6 Hz, 1 H), 7.38 (dd, J=2.6, 8.4 Hz, 1 H), 7.44 (d,J=7.2 Hz, 1 H), 7.86 (s, 2 H)

Example 29

[0336] Preparation ofN-[1-butyl-2-oxo-4-[2-isopropoxy-5-{3-(diethylamino)-1-propynyl}]phenyl-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)-urea:

[0337] The title compound was obtained in the same manner as in Example14 fromN-[1-butyl-2-oxo-4-(2-isopropoxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea.

[0338] The hydrochloride of the title compound was obtained in the samemanner as in Example 10.

[0339] M.p. 133-142° C.

[0340] IR (KBr) 3324, 2964, 2231, 1691, 1647, 1597 cm⁻¹

Example 30

[0341] Preparation of N-{1-butyl-2-oxo-4-(2-hydroxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,4-bis(methylthio)-6-methylpyridin-3-yl]urea:

[0342] The title compound was obtained in the same manner as in Example24 fromN-{1-butyl-2-oxo-4-(2-methoxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea.

[0343] M.p. 138-142° C.

Example 31

[0344] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl]urea:

[0345] The title compound was obtained in the same manner as in Example10 fromN-{1-butyl-2-oxo-4-(2-hydroxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,4-bis(methylthio)-6-methylpyridin-3-yl}ureaand isopropyl iodide.

[0346]¹H NMR δ (CD₃OD) 0.86 (t, J=7.2 Hz, 3 H), 1.14 (bs, 6 H), 1.30(tq, J=7.3, 7.3 Hz, 2 H), 1.60-1.70 (m, 2 H), 2.24 (s, 3 H), 2.29 (s, 3H), 2.34 (s, 3 H), 3.92 (t, J=7.2 Hz, 2 H), 4.47 (bs, 1 H), 6.19 (bs, 1H), 6.63 (bs, 1 H), 6.85 ((d, J=7.9 Hz, 1 H), 7.31-7.33 (m, 2 H), 7.37(d, J=7.21 Hz, 1 H)

Example 32

[0347] Preparation ofN-[1-butyl-2-oxo-4-{2-(3-pyridylmethoxy)-5-bromo}-phenyl-1,2-dihydropyridin-3-yl]-N′-(2,4-bis(methylthio)-6-methylpyridin-3-yl}urea:

[0348] The title compound was obtained in the same manner as in Example10 fromN-{1-butyl-2-oxo-4-(2-hydroxy-5-bromo)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureaand 3-chloromethylpyridine hydrochloride.

[0349]¹H NMR δ (DMSO-d₆) 0.94 (t, J=7.3 Hz, 3 H), 1.04 (bs, 12 H),1.32-1.37 (m, 2 H), 1.69-1.74 (m, 2 H), 2.79 (br, 2 H), 3.97 (br, 1 H),5.29 (s, 2 H), 6.26 (d, J=7.0 Hz, 1 H), 7.03 (d, J=7.7 Hz, 2 H), 7.09(d, J=8.8 Hz, 1 H), 7.15 (dd, J=7.7, 7.7 Hz, 1 H), 7.38 (d, J=2.4 Hz, 1H), 7.44-7.47 (m, 2 H), 7.79 (dd, J=5.1, 8.3 Hz, 1 H), 7.99 (s, 2 H),8.45 (d, J=8.3 Hz, 1 H), 8.78 (d, J=5.1 Hz, 1 H), 8.83 (s, 1 H)

Example 33

[0350] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}-urea:

[0351] The title compound was obtained in the same manner as in Example8 from1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl-1,2-dihydropyridin-3-carboxylicacid and 2,6-diisopropylaniline.

[0352] M.p. 82-84° C.

[0353] IR (KBr) 3324, 2962, 1711, 1643, 1580 cm⁻¹

Example 34

[0354] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,6-diisopropylphenyl)urea:

[0355] The title compound was obtained in the same manner as in Example26 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea.

[0356] M.p. 174-177° C.

[0357] IR (KBr) 3295, 2963, 1688, 1645, 1578 cm⁻¹

Example 35

[0358] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-4-methoxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl-3-yl)urea:

[0359] The title compound was obtained in the same manner as in Example10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)ureaand methyl iodide.

[0360] M.p. 170-172° C.

[0361] IR (KBr) 3326, 2959, 1706, 1647 cm⁻¹

Example 36

[0362] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}-urea:

[0363] The title compound was obtained in the same manner as in Example8 from 1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl-3-carboxylicacid and 3-amino-2,4-bis(methylthio)-6-methylpyridine.

[0364] M.p. 119-125° C.

[0365] IR (KBr) 3317, 2961, 1700, 1678, 16412, 1576 cm⁻¹

Example 37

[0366] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea:

[0367] The title compound was obtained in the same manner as in Example26 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}-urea.

[0368] M.p. 192-198° C.

[0369] IR (KBr) 3318, 2961, 1700, 1644 cm⁻¹

Example 38

[0370] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-4-methoxy)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea:

[0371] The title compound was obtained in the same manner as in Example10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}-ureaand methyl iodide.

[0372] M.p. 169-170° C.

[0373] IR (KBr) 3318, 2961, 1700, 1642, 1582 cm⁻¹

Example 39

[0374] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-5-benzyloxy)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,6-diisopropylphenyl)urea:

[0375] The title compound was obtained in the same manner as in Example8 from1-butyl-2-oxo-4-(2-isopropoxy-5-benzyloxy)phenyl-1,2-dihydropyridin-3-carboxylicacid and 2,6-diisopropylaniline.

[0376] M.p. 86-87° C. (flocculated and decomposed)

[0377] IR (KBr) 3318, 2963, 2868, 1643, 1581, 1499, 1466, 1382, 1207cm⁻¹

Example 40

[0378] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,6-diisopropylphenyl)urea:

[0379] The title compound was obtained in the same manner as in Example26 from N-(1-butyl-2-oxo-4-(2-isopropoxy-5-benzyloxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea.

[0380] M.p. 196-197° C. (decomposed)

[0381] IR (KBr) 3217, 2964, 1687, 1645, 1578, 1498, 1464, 1334, 1212cm⁻¹

Example 41

[0382] Preparation ofN-[1-butyl-2-oxo-4-{2-isopropoxy-5-(2-pyridylmethoxy)-phenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0383] The hydrochloride of the title compound was obtained in the samemanner as in Example 10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)-ureaand 2-chloromethylpyridine hydrochloride.

[0384] M.p. 184-185° C. (decomposed)

[0385] IR (KBr) 3252, 2964, 2869, 1646, 1602, 1520, 1467, 1382, 1213cm⁻¹

Example 42

[0386] Preparation ofN-[1-butyl-2-oxo-4-{2-isopropoxy-5-(3-pyridylmethoxy)-phenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0387] The hydrochloride of the title compound was obtained in the samemanner as in Example 10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)-ureaand 3-chloromethylpyridine hydrochloride.

[0388] M.p. 138-140° C. (flocculated and decomposed)

[0389] IR (KBr) 3250, 3066, 2964, 2869, 1642, 1606, 1545, 1498, 1468,1383 cm⁻¹

Example 43

[0390] Preparation ofN-[1-butyl-2-oxo-4-{2-isopropoxy-5-(2-piperidinoethoxy)-phenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0391] The hydrochloride of the title compound was obtained in the samemanner as in Example 10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)-ureaand 1-(2-chloroethyl)piperidine hydrochloride.

[0392] M.p. 130-132° C. (flocculated and decomposed)

[0393] IR (KBr) 3324, 2964, 2869, 1647, 1587, 1489, 1382, 1216 cm⁻¹

Example 44

[0394] Preparation ofN-[1-butyl-2-oxo-4-{2-isopropoxy-5-(2-morpholino-ethoxy)phenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0395] The hydrochloride of the title compound was obtained in the samemanner as in example 10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)-ureaand 4-(2-chloroethyl)morpholine hydrochloride.

[0396] M.p. 96-98° C. (flocculated and decomposed)

[0397] IR (KBr) 3327, 2964, 2870, 1616, 1583, 1499, 1467, 1383 cm¹

Example 45

[0398] Preparation ofN-[1-butyl-2-oxo-4-{2-isopropoxy-5-(2-diethylamino-ethoxy)phenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0399] The hydrochloride of the title compound was obtained in the samemanner as in Example 10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)-ureaand 2-chlorotriethylamine hydrochloride.

[0400] M.p. 73-75° C. (flocculated and decomposed)

[0401] IR (KBr) 3318, 2963, 2870, 1646, 1582, 1498, 1468, 1383, 1214cm⁻¹

Example 46

[0402] Preparation ofN-[1-butyl-2-oxo-4-]2-isopropoxy-5-{3-(1,2,4-triazol-1-yl)propoxy}phenyl]-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)-urea:

[0403] The hydrochloride of the title compound was obtained in the samemanner as in Example 10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)-ureaand 1-(3-bromopropyl)-1,2,4-triazole.

[0404] M.p. 84-86° C. (flocculated and decomposed)

[0405] IR (KBr) 3320, 2964, 2870, 1645, 1582, 1500, 1467, 1383, 1214cm⁻¹

Example 47

[0406] Preparation ofN-[1-butyl-2-oxo-4-{2-isopropoxy-5-(4-pyridylmethoxy)-phenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0407] The hydrochloride of the title compound was obtained in the samemanner as in Example 10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl) -urea and 4-chloromethylpyridine hydrochloride.

[0408] M.p. 95-97° C. (decomposed)

[0409] IR (KBr) 3254, 2963, 2869, 1644, 1605, 1501, 1468, 1383, 1224cm⁻¹

Example 48

[0410] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-4-methoxy)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea:

[0411] To a solution ofN-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)-phenyl-1,2-dihydropyridin-3-yl}-N′-(2,4-bis(methylthio)-6-methylpyridin-3-yl}urea(880 mg, 1.62 mmol) in dimethyolformamide (10 ml) were added potassiumcarbonate (689 mg, 4.99 mmol) and methyl iodide (1.55 ml, 2.49 mmol),and the mixture was stirred at about 50° C. for 6 hours. The mixture wasdiluted with ethyl acetate, and the reaction was quenched by addition ofwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and a saturated aqueous sodium chloridesolution, and the solvent was evaporated under reduced pressure to givea crude product. The crude product thus obtained was purified by silicagel column chromatography (ethyl acetate), and crystallized from ethylacetate/diethyl ether to give the title compound.

[0412] The crystals thus obtained were dissolved in tetrahydrofuran (4ml) under heating, and converted into a hydrochloride thereof with 1 Nhydrochloric acid/diethyl ether (1 ml). To the mixture was added diethylether (10 ml) for crystallization, and the crystals were collected byfiltration to give the hydrochloride of the title compound (391 mg, 0.68mmol).

[0413] M.p. 212-214° C. (flocculated and decomposed)

[0414] IR (KBr)3245, 2959, 1691, 1611, 1530, 1442, 1382, 1304 cm⁻¹

Example 49

[0415] Preparation ofN-[1-butyl-2-oxo-4-{2-isopropoxy-4-(3-pyridylmethoxy)-phenyl)-1,2-dihydropyridin-3-yl]-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea:

[0416] The hydrochloride of the title compound was obtained in the samemanner as in Example 10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}ureaand 3-chloromethylpyridine hydrochloride.

[0417] M.p. 176-178° C. (flocculated and decomposed)

[0418] IR (KBr) 3424, 2958, 1689, 1608, 1570, 1430, 1383, 1304 cm⁻¹

Example 50

[0419] Preparation ofN-[1-butyl-2-oxo-4-{2-isopropoxy-4-(2-piperidinoethoxy)-phenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0420] The hydrochloride of the title compound was obtained in the samemanner as in Example 10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)-ureaand 1-(2-chloroethyl)piperidine hydrochloride.

[0421] M.p. 122-124° C. (flocculated and decomposed)

[0422] IR (KBr) 3338, 2963, 1646, 1578, 1508, 1466, 1301, 1190, 1110cm⁻¹

Example 51

[0423] Preparation ofN-[1-butyl-2-oxo-4-(2-isopropoxy-4-(3-piperidinopropoxy)phenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)-urea:

[0424] The hydrochloride of the title compound was obtained in the samemanner as in Example 10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)-ureaand 1-(3-chloropropyl)piperidine hydrochloride.

[0425] M.p. 116-118° C. (flocculated and decomposed)

[0426] IR (KBr) 3400, 2962, 1644, 1578, 1466, 1383, 1300, 1190, 1111,926 cm⁻¹

Example 52

[0427] Preparation ofN-[1-butyl-2-oxo-4-{2-isopropoxy-4-(2-morpholinoethoxy)phenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0428] The hydrochloride of the title compound was obtained in the samemanner as in Example 10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)-ureaand 4-(2-chloroethyl)morpholine hydrochloride.

[0429] M.p. 117-119° C. (flocculated and decomposed)

[0430] IR (KBr) 3400, 2966, 1644, 1578, 1465, 1384, 1301, 1190, 1134,1107 cm⁻¹

Example 53

[0431] Preparation ofN-[1-butyl-2-oxo-4-[2-isopropoxy-4-{3-(1,2,4-triazol-1-yl)propoxyphenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)-urea:

[0432] The hydrochloride of the title compound was obtained in the samemanner as in Example 10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxy)phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)-ureaand 1-(3-bromopropyl)-1,2,4-triazole.

[0433] M.p. 98-104° C. (flocculated and decomposed)

[0434] IR (KBr) 3328, 2964, 1643, 1576, 1508, 1466, 1384, 1301, 1190,1112 cm⁻¹

Example 54

[0435] Preparation ofN-{1-butyl-2-oxo-4-(2-methoxy-5-fluorophenyl)-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea:

[0436] The title compound was obtained in- the same manner as in Example8 from1-butyl-2-oxo-4-(2-methoxy-5-fluorophenyl)-1,2-dihydropyridine-3-carboxylicacid and 2,6-diisopropylaniline.

[0437] M.p. 165-166° C. (flocculated and decomposed)

[0438] IR (KBr) 3321, 2961, 2872, 1701, 1644, 1579, 1517, 1467, 1258,1210 cm⁻¹

Example 55

[0439] Preparation ofN-{1-butyl-2-oxo-4-(2-methoxy-5-fluorophenyl)-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea:

[0440] The title compound was obtained in the same manner as in Example8 from1-butyl-2-oxo-4-(2-methoxy-5-fluorophenyl)-1,2-dihydropyridine-3-carboxylicacid and 3-amino-2,4-bis(methylthio)-6-methylpyridine.

[0441] M.p. 194-196° C.

[0442] IR (KBr) 3319, 2958, 2928, 1701, 1642, 1579, 1500, 1434, 1212cm⁻¹

Example 56

[0443] Preparation of N-{1-butyl-2-oxo-4-(2-methoxyphenyl)-1,2-dihydropyridin-3-yl}-N′-{2,4-bis(methylthio)-6-methylpyridin-3-yl}urea:

[0444] The title compound was obtained in the same manner as in Example8 from1-butyl-2-oxo-4-(2-methoxyphenyl)-1,2-dihydropyridine-3-carboxylic acidand 3-amino-2,4-bis(methylthio)-6-methylpyridine.

[0445] M.p. 196-199° C.

[0446] IR (KBr) 3318, 2958, 2925, 2872, 1701, 1641, 1578, 1516, 1255,1211 cm⁻¹

Example 57

[0447] Preparation ofN-[1-butyl-2-oxo-4-{2-(3-dimethylaminopropoxy)phenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0448] a) Preparation of1-butyl-2-oxo-3-amino-4-(2-methoxyphenyl)-1,2-dihydropyridine:

[0449] The title compound was obtained in the same manner as in Example3 from1-butyl-2-oxo-3-carbamoyl-4-(2-methoxyphenyl)-1,2-dihydropyridine.

[0450]¹H NMR δ (DMSO-d₆) 0.93 (t, J=7.3 Hz, 3 H), 3.76 (s, 3 H), 4.53(s, 2 H)

[0451] b) Preparation of1-butyl-2-oxo-3-amino-4-(2-hydroxyphenyl)-1,2-dihydropyridine:

[0452] The title compound was obtained in the same manner as in Example9 from 1-butyl-2-oxo-3-amino-4-(2-methoxyphenyl)-1,2-dihydropyridine.

[0453]¹H NMR δ (DMSO-d₆) 0.90 (t, J=7.3 Hz, 3 H), 3.89 (d, J=5.6, 2 H),7.14-7.22 (m, 2 H)

[0454] c) Preparation of1-butyl-2-oxo-3-amino-4-{2-(3-dimethylaminopropoxy)phenyl}-1,2-dihydropyridine:

[0455] The title compound( was obtained in the same manner as in Example10 from 1-butyl-2-oxo-3-amino-4-(2-hydroxyphenyl)-1,2-dihydropyridineand 3-dimethylaminopropyl chloride hydrochloride.

[0456]¹H NMR δ (DMSO-d₆) 0.89 (t, J=7.3 Hz, 3 H), 2.10 (s, 6 H)

[0457] d) Preparation ofN-[1-butyl-2-oxo-4-{2-(3-dimethylaminopropoxy)-phenyl-1,2-dihydropyridin-3-yl}-N′-(2,6-diisopropylphenyl)urea:

[0458] The title compound was obtained in the same manner as in Example4 from1-butyl-2-oxo-3-amino-4-{2-(3-dimethylaminopropoxy)-phenyl}-1,2-dihydropyridineand 2,6-diisopropylaniline.

[0459]¹H NMR δ (DMSO-d₆) 0.88-1.07 (m, 15 H), 2.18 (s, 6 H)

[0460] The title compound was converted into a hydrochloride thereof inthe same manner as in Example 10.

[0461]¹H NMR δ (DMSO-d₆) 0.85-1.10 (m, 15 H), 1.28-1.40 (m, 2 H), 2.51(s, 3 H), 2.53 (s, 3 H), 3.00-3.10 (m, 2 H)

[0462] IR (KBr) 3316, 2952, 2869, 1645, 1580, 1523, 1467, 1383, 1227cm⁻¹

Example 58

[0463] Preparation ofN-[1-butyl-2-oxo-4-{2-(2-piperidinoethoxy-5-methoxyphenyl)}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0464] a) Preparation of1-butyl-2-oxo-3-amino-4-(2-benzyloxy-5-methoxyphenyl)-1,2-dihydropyridine:

[0465] The title compound was obtained in the same manner as in Example3 from1-butyl-2-oxo-3-carbamoyl-4-(2-benzyloxy-5-methoxyphenyl)-1,2-dihydropyridine.

[0466]¹H NMR δ (DMSO-d₆) 0.90 (t, J=7.3 Hz, 3 H), 3.71 (s, 3 H), 4.65(s, 2 H), 5.02 (s, 2 H), 6.03 (d, J=7.0 Hz, 1 H)

[0467] b) Preparation of1-butyl-2-oxo-3-amino-4-(2-hydroxy-5-methoxyphenyl)-1,2-dihydropyridine:

[0468] To a solution of1-butyl-2-oxo-3-amino-4-(2-benzyloxy-5-methoxyphenyl)-1,2-dihydropyridine(1.20 g, 3.17 mmol) in methanol (20 ml) was added 10% Pd/C (50% wet, 300mg), and the mixture was stirred at room temperature for one hour underhydrogen atmosphere. After confirming the completion of the reaction,the reaction solution was filtered through a cerite pad, and thefiltrate was concentrated to give the title compound (883 mg) as paleyellow amorphous, which was used in the subsequent reaction withoutfurther purification.

[0469]¹H NMR δ (DMSO-d₆) 0.94 (t, J=7.3 Hz, 3 H), 3.68 (s, 3 H), 4.68(s, 2 H)

[0470] c) Preparation of1-butyl-2-oxo-3-amino-4-{2-(2-piperidinoethoxy)-5-methoxyphenyl}-1,2-dihydropyridine:

[0471] The title compound was obtained in the same manner as in

Example 10 from1-butyl-2-oxo-3-amino-4-(2-hydroxy-5-methoxyphenyl)-1,2-dihydropyridineand 1-(2-chloroethyl)piperidine hydrochloride.

[0472]¹H NMR δ (DMSO-d₆) 0.91 (t, J=3 Hz, 3 H), 1.25-1.43 (m, 8 H),1.61-1.68 (m, 2 H), 2.29-2.32 (m, 2 H), 2.50-2.56 (m, 2 H), 3.72 (s, 3H), 4.71 (br s, 2 H)

[0473] d) Preparation ofN-[1-butyl-2-oxo-4-{2-(2-piperidinoethoxy)-5-methoxyphenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0474] The title compound was obtained in the same manner as in Example4 from1-butyl-2-oxo-3-amino-4-{2-(2-piperidinoethoxy)-5-methoxyphenyl}-1,2-dihydropyridineand 2,6-diisopropylaniline.

[0475]¹H NMR δ (DMSO-d₆) 0.82-0.98 (m, 15 H), 1.23-1.42 (m, 8 H),1.62-1.67 (m, 2 H), 2.82-2.87 (m, 2 H), 3.67 (s, 3 H), 3.91-3.97 (m, 4H)

[0476] The title compound was converted into a hydrochloride thereof inthe same manner as in Example 10.

[0477] M.p. 146-148° C.

[0478]¹H NMR δ (DMSO-d₆) 0.82-1.14 (m, 19 H), 1.26-1.37 (m, 2 H),1.60-1.69 (m, 2 H), 3.73 (s, 3 H), 7.89 (s, 1 H), 7.98 (s, 1 H)

[0479] IR (KBr) 3307, 2961, 2870, 1646, 1587, 1499, 1467, 1383, 1216cm⁻¹

Example 59

[0480] Preparation ofN-]1-butyl-2-oxo-4-{2-(2-morpholinoethoxy)-5-methoxy-phenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0481] a) Preparation of1-butyl-2-oxo-3-amino-4-{2-(2-morpholinoethoxy)-5-methoxyphenyl}-1,2-dihydropyridine:

[0482] The title compound was obtained in the same manner as in Example10 from1-butyl-2-oxo-3-amino-4-(2-hydroxy-5-methoxyphenyl)-1,2-dihydropyridineand 4-(2-chloroethyl)morpholine hydrochloride.

[0483]¹H NMR δ (DMSO-d₆) 0.90 (t, J=7.3 Hz, 3 H), 3.71 (s, 3 H), 4.68(s, 3 H)

[0484] b) Preparation ofN-[1-butyl-2-oxo-4-{2-(2-morpholinoethoxy)-5-methoxyphenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0485] The title compound was obtained in the same manner as in Example4 from1-butyl-2-oxo-3-amino-4-{2-(2-morpholinoethoxy)-5-methoxyphenyl}-1,2-dihydropyridineand 2,6-diisopropylaniline.

[0486]¹H NMR δ (DMSO-d₆) 0.85-0.99 (m, 15 H), 2.82-2.90 (m, 2 H),3.46-3.52 (m, 4 H), 3.68 (s, 3 H), 3.91-4.06 (m, 4 H)

[0487] The title compound was converted into a hydrochloride thereof inthe same manner as in Example 10.

[0488] M.p. 156-158° C. (decomposed)

[0489]¹H NMR δ (DMSO-d₆) 0.90-1.08 (m, 15 H), 2.80-3.05 (m, 2 H),3.20-3.45 (m, 2 H), 3.67-3.76 (m, H), 4.27-4.33 (br, 2 H)

[0490] IR (KBr) 3308, 2963, 2871, 1813, 1646, 1590, 1500, 1466, 1216cm⁻¹

Example 60

[0491] Preparation ofN-[1-butyl-2-oxo-4-[2-{3-(1,2,4-triazol-1-yl)propoxy}-5-methoxyphenyl]-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)-urea:

[0492] a) Preparation of1-butyl-2-oxo-3-amino-4-[2-{3-(1,2,4-triazol-1-yl)propoxy}-5-methoxyphenyl]-1,2-dihydropyridine:

[0493] The title compound was obtained in the same manner as in Example10 from1-butyl-2-oxo-3-amino-4-(2-hydroxy-5-methoxyphenyl)-1,2-dihydropyridineand 1-(3-bromopropyl)-1,2,4-triazole.

[0494]¹H NMR δ (DMSO-d₆) 0.88 (t, J=7.3 Hz, 3 H), 3.68 (s, 3 H), 4.70(s, 2 H), 7.93 (s, 1 H), 8.36 (s, 1 H)

[0495] b) Preparation ofN-[1-butyl-2-oxo-4-[2-{3-(1,2,4-triazol-1-yl)-propoxy}-5-methoxyphenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0496] The title compound was obtained in the same manner as in Example4 from1-butyl-2-oxo-3-amino-4-[2-{3-(1,2,4-triazol-1-yl)-propoxy}-5-methoxyphenyl]-1,2-dihydropyridineand 2,6-diisopropylaniline.

[0497]¹H NMR δ (DMSO-d₆) 0.85-1.02 (m, 15 H), 2.75-2.90 (m, 2 H), 3.68(s, 3 H), 7.94 (s, 1 H), 8.27 (s, 1 H)

[0498] The title compound was converted into a hydrochloride thereof inthe same manner as in Example 10.

[0499]¹H NMR δ (DMSO-d₆) 0.84-1.05 (m, 15 H), 1.23-1.35 (m, 2 H),2.05-2.12 (m, 2 H), 3.68 (s, 3 H), 3.84-3.96 (m, 4 H), 7.82 (s, 1 H),7.85 (s, 1 H), 8.04 (s, 1 H), 8.46 (s, 1 H)

[0500] IR (KBr) 3307, 2963, 2871, 1642, 1580, 1502, 1468, 1217 cm⁻¹

Example 61

[0501] Preparation ofN-[1-butyl-2-oxo-4-{2-(3-piperidinopropoxy)-5-methoxyphenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0502] a) Preparation of1-butyl-2-oxo-3-amino-4-{2-(3-piperidinopropoxy)-5-methoxyphenyl}-1,2-dihydropyridine:

[0503] The title compound was obtained in the same manner as in Example10 from1-butyl-2-oxo-3-amino-4-(2-hydroxy-5-methoxyphenyl)-1,2-dihydropyridineand 1-(3-chloropropyl)piperidine hydrochloride.

[0504]¹H NMR δ (DMSO-d₆) 0.90 (t, J=7.3 Hz, 3 H), 1.22-1.45 (m, 8 H),1.57-1.74 (m, 4 H), 3.72 (s, 3 H), 3.86-3.92 (m, 4 H), 4.61 (s, 2 H)

[0505] b) Preparation ofN-1-butyl-2-oxo-4-{2-(3-piperidinopropoxy)-5-methoxyphenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0506] The title compound was obtained in the same manner as in Example4 from1-butyl-2-oxo-3-amino-4-{2-(3-piperidinopropoxy)-5-methoxyphenyl}-1,2-dihydropyridineand 2,6-diisopropylaniline.

[0507]¹H NMR δ (DMSO-d₆) 0.85-1.11 (m, 15 H), 1.29-1.44 (m, 8 H),1.63-1.73 (m, 4 H), 2.81-2.87 (m, 2 H), 3.67 (s, 3 H), 3.86-3.97 (m, 4H), 7.68 (s, 1 H), 7.77 (s, 1 H)

[0508] The title compound was converted into a hydrochloride thereof inthe same manner as in Example 10.

[0509] M.p. 173-176° C. (decomposed)

[0510]¹H NMR δ (DMSO-d₆) 0.80-1.10 (m, 15 H), 1.95-1.99 (m, 2 H),2.76-2.82 (m, 2 H), 2.94-3.02 (m, 2 H), 3.12-3.16 (m, 2 H), 3.70 (s, 3H), 3.80-4.05 (m, 4 H), 7.91 (s, 1 H), 8.03 (s, 1 H)

[0511] IR (KBr) 3244, 2960, 2869, 1694, 1596, 1499, 1468, 1215 cm⁻¹

Example 62

[0512] Preparation ofN-[1-butyl-2-oxo-4-{2-(3-pyridylmethoxy)-5-methoxyphenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0513] a) Preparation of1-butyl-2-oxo-3-amino-4-{2-(3-pyridylmethoxy)-5-methoxyphenyl}-1,2-dihydropyridine:

[0514] The title compound was obtained in the same manner as in Example10 from1-butyl-2-oxo-3-amino-4-(2-hydroxy-5-methoxyphenyl)-1,2-dihydropyridineand 3-chloromethylpyridine hydrochloride.

[0515]¹H NMR δ (DMSO-d₆) 0.89 (t, J=7.3 Hz, 3 H), 3.72 (s, 3 H), 4.69(s, 2 H), 5.07 (s, 2 H)

[0516] b) Preparation ofN-[1-butyl-2-oxo-4-{2-(3-pyridylmethoxy)-5-methoxyphenyl}-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea:

[0517] The title compound was obtained in the same manner as in Example4 from1-butyl-2-oxo-3-amino-4-{2-(3-pyridylmethoxy)-5-methoxyphenyl}-1,2-dihydropyridineand 2,6-diisopropylaniline.

[0518]¹H NMR δ (DMSO-d₆) 0.82-1.30 (m, 15 H), 3.69 (s, 3 H), 5.03 (s, 2H), 6.82-6.86 (m, 2 H), 6.98-7.14 (m, 4 H), 7.79 (s, 1 H), 7.85 (s, 1H), 8.54 (s, 1 H)

[0519] The title compound was converted into a hydrochloride thereof inthe same manner as in Example 10.

[0520] M.p. 138-141° C. (decomposed)

[0521]¹H NMR δ (DMSO-d₆) 0.80-1.08 (m, 15 H), 1.27-1.37 (m, 2 H),1.62-1.70 (m, 2 H), 2.70-2.90 (m, 2 H), 3.70 (s, 3 H), 5.21 (s, 2 H),8.81 (s, 1 H)

[0522] IR (KBr) 2870, 1756, 1712, 1644, 1580, 1500, 1469, 1197 cm⁻¹

Example 63

[0523] Preparation ofN-1-butyl-2-oxo-4-(2-isopropoxy-5-benzyloxyphenyl)-1,2-dihydropyridin-3-yl}-N′-{2-tert-butyl-5-(1-pyrazolylmethyl)phenyl}-urea:

[0524] The title compound was obtained in the same manner as in Example8 from1-butyl-2-oxo-4-(2-isopropoxy-5-benzyloxyphenyl)-1,2-dihydropyridine-3-carboxylicacid and 2-tert-butyl-5-(1-pyrazolylmethyl)aniline, and further thehydrochloride thereof was obtained in the same manner as in Example 10.

[0525] M.p. 102-103° C.

[0526] IR (KBr) 2963, 2872, 1645, 1578, 1528, 1498 cm⁻¹

Example 64

[0527] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxyphenyl)-1,2-dihydropyridin-3-yl}-N′-{2-tert-butyl-5-(1-pyrazolylmethyl)phenyl}urea:

[0528] The title compound was obtained in the same manner as in Example58 b) fromN-{1-butyl-2-oxo-4-(2-isopropoxy-5-benzyloxyphenyl)-1,2-dihydropyridin-3-yl}-N′-{2-tert-butyl-5-(1-pyrazolylmethyl)phenyl}urea,and further the hydrochloride thereof was obtained in the same manner asin Example 10.

[0529] M.p. 142-143° C.

[0530] IR (KBr) 2968, 2873, 1645, 1578, 1539, 1497 cm⁻¹

Example 65

[0531] Preparation of N-{1-butyl-2-oxo-4-(2-isopropoxy-5-methoxyphenyl)-1,2-dihydropyridin-3-yl}-N′-{2-tert-butyl-5-(1-pyrazolylmethyl)phenyl}urea:

[0532] The title compound was obtained in the same manner as in Example48 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-5-hydroxyphenyl)-1,2-dihydropyridin-3-yl}-N′-{2-tert-butyl-5-(1-pyrazolylmethyl)phenyl}-urea,and further the hydrochloride thereof was obtained in the same manner asin Example 10.

[0533] M.p. 99-100° C.

[0534] IR (KBr) 2963, 2873, 1644, 1580, 1421 cm⁻¹

[0535] Example 66

[0536] Preparation ofN-[1-butyl-2-oxo-4-{2-isopropoxy-5-(3-pyridylmethoxy)-phenyl}-1,2-dihydropyridin-3-yl]-N′-{2-tert-butyl-5-(1-pyrazolylmethyl)-phenyl}urea:

[0537] The hydrochloride of the title compound was obtained in the samemanner as in Example 10 fromN-{1-butyl-2-oxo-5-(2-isopropoxy-5-hydroxyphenyl)-1,2-dihydropyridin-3-yl}-N′-{2-tert-butyl-5-(1-pyrazolylmethyl)phenyl}ureaand 3-chloromethylpyridine.

[0538]¹H NMR δ (DMSO-d₆) 0.94 (t, J=7.3 Hz, 3 H), 1.13 (d, J=6.0 Hz, 6H), 1.17 (s, 9 H), 3.96 (t, J=7.0 Hz, 2 H), 7.20 (d, J=8.8 Hz, 1 H)

Example 67

[0539] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxyphenyl)-1,2-dihydropyridin-3-yl}-N′-{2-tert-butyl-5-(1-imidazolylmethyl)phenyl}-urea:

[0540] The title compound was obtained in the same manner as in Example8 from1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxyphenyl)-1,2-dihydropyridine-3-carboxylicacid and 2-tert-butyl-5-(1-imidazolylmethyl)aniline, and thehydrochloride thereof was further obtained in the same manner as inExample 10.

[0541] M.p. 138-140° C.

[0542] IR (KBr) 2963, 2871, 1643, 1607, 1574, 1541 cm⁻¹

Example 68

[0543] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxyphenyl)-1,2-dihydropyridin-3-yl}-N′-(2-tert-butyl-5-(1-imidazolylmethyl)phenyl}urea:

[0544] The title compound was obtained in the same manner as in Example58 b) fromN-{1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxyphenyl)-1,2-dihydropyridin-3-yl}-N′-{2-tert-butyl-5-(1-imidazolylmethyl)phenyl}urea,and the hydrochloride thereof was further obtained in the same manner asin Example 10.

[0545] M.p. 162-163° C.

[0546] IR (KBr) 2962, 2872, 1642, 1610, 1579, 1541 cm⁻¹

Example 69

[0547] Preparation ofN-{1-butyl-2-oxo-4-(2-isopropoxy-4-methoxyphenyl)-1,2-dihydropyridin-3-yl}-N′-{2-tert-butyl-5-(1-imidazolylmethyl)phenyl}urea:

[0548] The title compound was obtained in the same manner as in Example48 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxyphenyl)-1,2-dihydropyridin-3-yl}-N′-{2-tert-butyl-5-(1-imidazolylmethyl)phenyl}-urea,and further they hydrochloride thereof was obtained in the same manneras in Example 10.

[0549] M.p. 147-148° C.

[0550] IR (KBr) 2962, 2871, 1646, 1604, 1508, 1466 cm⁻¹

Example 70

[0551] Preparation ofN-[1-butyl-2-oxo-4-{2-isopropoxy-4-(3-pyridylmethoxy)-phenyl}-1,2-dihydropyridin-3-yl]-N′-{2-tert-butyl-5-(1-imidazolylmethyl)-phenyl}urea:

[0552] The title compound was obtained in the same manner as in Example10 fromN-{1-butyl-2-oxo-4-(2-isopropoxy-4-hydroxyphenyl)-1,2-dihydropyridin-3-yl}-N′-{2-tert-butyl-5-(1-imidazolylmethyl)phenyl}-ureaand 3-chloromethylpyridine, and the hydrochloride thereof was furtherobtained in the same manner as in Example 10.

[0553]¹H NMR δ (DMSO-d₆) 0.94 (t, J=7.3 Hz, 3 H), 1.13 (d, J=6.0 Hz, 6H), 1.17 (s, 9 H), 5.15 (s, 2 H), 5.24 (s, 2 H), 7.20 (d, J=8.8 Hz)

[0554] M.p. 1 1. 1-112° C.

[0555] IR (KBr) 2964, 2872, 1643, 1607, 1577, 1543 cm⁻¹

[0556] Reference Example 1

[0557] Preparation of1-butyl-3-carbamoyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine:

[0558] A mixture of1-butyl-3-ethoxycarbonyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine(45.0 g, 120 mmol), formamide (15.5 ml, 390 mmol) and dimethylformamide(120 ml) was dissolved at 60° C., and thereto was added a 25% solutionof sodium methoxide in methanol (108 ml, 390 mmol), and the mixture wasstirred at 60° C. for 9 hours. The mixture was cooled to 0° C., andthereto was added water (1.2 liter), and the mixture was stirred for 15minutes. The precipitated solid was collected by filtration, washed withethanol, and to dried to give the title compound (37.8 g, yield; 87 %)as white powder.

[0559] M.p. 239-240° C.

[0560] Reference Example 2

[0561] Preparation of1-butyl-3-carbamoyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine:

[0562] To a suspension of1-butyl-3-carboxy-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine(10.0 g, 28.4 mmol) in toluene (300 ml) was added thionyl chloride (2.95g, 34.1 mmol), and the mixture was stirred at room temperature for 0.5hour, and then stirred at 90-100° C. for 6 hours. After allowed to cool,the mixture was concentrated under reduced pressure. To the concentratedresidue was added toluene, and the mixture was concentrated again underreduced pressure. The concentrated residue was dissolved in dioxane (100ml), and the mixture was added dropwise into conc. aqueous ammonia (80ml) in an ice-bath. The mixture was stirred at room temperature for 6hours, and poured into water. The precipitated crystals were collectedby filtration, dispersed in ethanol (50 ml), and the mixture was stirredfor one hour. The solid thus obtained was collected by filtration togive the title compound (9.12 g, 24.8 mmol, yield; 87%) as colorlesspowder.

[0563] M.p. 239-240° C.

[0564] Reference Example 3

[0565] Preparation of 2-(butylamino) -3-(3-methoxybenzoyl)pyridine:

[0566] To a suspension of sodium hydride (60%, 578 mg, 14.5 mmol) intetrahydrofuran (15 ml) was added dropwise a solution of3-(2-aminopyridyl)-(3-methoxyphenyl)ketone (3.00 g, 13.1 mmol) intetrahydrofuran (24 ml) under ice-cooling, and further thereto was addeddropwise a solution of butyl iodide (3.63 g, 19.7 mmol) intetrahydrofuran at room temperature, and the mixture was stirred at50-60° C. for 6 hours. The mixture was cooled to room temperature, andthereto was added water. The mixture was extracted with toluene, andwashed successively with a 5% aqueous sodium hydrogen carbonatesolution, water and a 5% aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate/hexane=¼) to give the title compound (2.96 g, 10.4 mmol, 79%) asyellow oil.

[0567]¹H NMR δ (CDCl₃) 0.98 (3 H, t, J=7.3 Hz), 1.43-1.55 (2 H, m),1.65-1.75 (2 H, m), 3.56-3.62 (2 H, m), 3.85 (3 H, s), 6.47 (1H, dd,J=7.9 Hz, 4.8 Hz), 7.06-7.13 (3 H, m), 7.37 (1 H, dd, J=8.3 Hz, 8.3 Hz),7.76 (1 H, dd, J=7.9 Hz, 2.0 Hz), 8.32 (1 H, dd, J=4.8 Hz, 2.0 Hz), 8.82(1 H, brs)

[0568] Reference Example 4

[0569] Preparation of2{(N-butyl-N-phthalimideacetyl)amino}-3-(3-methoxybenzoyl)pyridine:

[0570] To a suspension of N-phthaloylglycine (4.76 g, 23.2 mmol) intoluene (24 ml) were added thionyl chloride (5.08 ml, 69.6 mmol) anddimethylformamide (0.4 ml), and the mixture was stirred at 50-60° C. for30 minutes. After allowed to cool, the solvent was evaporated underreduced pressure. The residue was subjected twice to azeotropicdistillation with toluene, and the residue was suspended in dioxane (20ml). The mixture was added dropwise to a solution of2-(butylamino)-3-(3-methoxybenzoyl)pyridine (3.30 g, 11.6 mmol) inpyridine (27 ml) at room temperature. The mixture was stirred at 50-60°C. for one hour, stirred at 60-70° C. for one hour, and further stirredat 70-80° C. for one hour. The mixture was cooled to room temperature,and water was added therein, and the mixture was extracted with ethylacetate. The extract was washed with successively with 1 N hydrochloricacid, water, a 5% aqueous sodium hydrogen carbonate solution, and a 5%aqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, concentrated under reduced pressure, and purified by silica gelcolumn chromatography (ethyl acetate/hexane=½) to give the titlecompound (3.77 g, 8.00 mmol, 69%) as yellow amorphous.

[0571]¹H NMR δ (CDCl₃) 0.74 (3 H, t, J=7.3 Hz, 3 Hz), 1.11-1.23 (2 H,m), 1.36-1.43 (2 H, m), 3.36-3.46 (2 H, m), 3.88 (3 H, s), 4.45 (2 H,s), 7.11-7.25 (2 H, m), 7.27-7.51 (2 H, m), 7.67-7.75 (3 H, m),7.77-7.94 (3 H, m), 8.74 (1 H, s)

[0572] Reference Example 5

[0573] Preparation of1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihydropyridine-3-carboxylic acid:

[0574] a) Preparation of ethyl 2-cyano-3-(3-methoxy)phenyl-crotonate:

[0575] To a solution of 3-methoxyacetophenone (25 g, 166 mmol) intoluene (40 ml) were added ethyl cyanoacetate (18.8 g, 166 mmol),ammonium acetate (2.6 g, 33.2 mmol) and acetic acid (7.6 ml, 133 mmol),and the mixture was stirred under reflux for about 6 hours. To thereaction solution was added water, and the mixture was extracted withethyl acetate. The extract was washed with a saturated aqueous sodiumchloride solution and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (ethyl acetate:hexane=1:10)to give the title compound (13.9 g, yield; 34%) as brown oil.

[0576]¹H NMR δ (CDCl₃) 1.14 and 1.26 (t and t, J=7.2 and 7.2 Hz, 3 H),2.53 and 2.68 (s and s, 3 H), 3.80 and 3.83 (s and s, 3 H), 4.12 and4.34 (q and q, J=7.2 and 7.2 Hz, 2 H), 6.68-6.75 and 6.91-7.02 (m and m,3 H), 7.26-7.39 (m, 1 H)

[0577] b) Preparation of ethyl2-oxo-4-(3-methoxy)phenyl-1,2-dihydropyridine-3-carboxylate:

[0578] To ethyl 2-cyano-3-(3-methoxy)phenyl-crotonate (12.3 g, 50.1mmol) was added N,N-dimethylformamide dimethyl acetal (17 ml), and themixture was stirred at room temperature for about 5 hours. The solventwas evaporated under reduced pressure, and thereto was added 80% aqueousacetic acid solution (625 ml), and the mixture was stirred under refluxfor about 2 hours. The solvent was evaporated under reduced pressure,and water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The extract was washed with a saturatedaqueous sodium chloride solution, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresulting residue was purified by silica gel column chromatography(ethyl acetate:hexane=2:1) to give the title compound (8.69 g, yield;67%) as brown crystals.

[0579] M.p. 153-156° C.

[0580] IR (KBr) 3433, 1727, 1646, 1531 cm⁻¹

[0581] c) Preparation of ethyl1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihydropyridine-3-carboxylate:

[0582] To a solution of ethyl2-oxo-4-(3-methoxy)phenyl-1,2-dihydropyridine-3-carboxylate (7.69 g,29.9 mmol) in DMF (60 ml) were added potassium carbonate (12.4 g, 89.7mmol) and butyl iodide (5.1 ml, 44.9 mmol), and the mixture was stirredat room temperature for about 3 hours. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The extractwas washed with a saturated aqueous sodium chloride solution, and driedover magnesium sulfate. The solvent was evaporated under reducedpressure, and the resulting residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:1) to give the title compound(7.65 g, yield; 78%) as brown oil.

[0583]¹H NMR δ (CDCl₃) 0.97 (t, J=7.3 Hz, 3 H), 1.11 (t, J=7.2 Hz, 3 H),1.37-1.47 (m, 2 H), 1.73-1.83 (m, 2 H), 3.82 (s, 3 H), 3.97 (t, J=7.3Hz, 2 H), 4.19 (q, J=7.2 Hz, 2 H), 6.23 (d, J=7.0 Hz, 1 H), 6.92-7.01(m, 3 H), 7.26-7.34 (m, 2 H)

[0584] IR (neat) 2960, 1732, 1650, 1600 cm⁻¹

[0585] d) Preparation of1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihydropyridine-3-carboxylic acid:

[0586] To a solution of ethyl1-butyl-2-oxo-4-(3-methoxy)phenyl-1,2-dihydropyridine-3-carboxylate(6.05 g, 18.4 mmol) in ethanol (30 ml) was added sodium hydroxide (2.94g, 73.5 mmol), and the mixture was stirred under reflux for about 7hours. The pH value of the mixture was adjusted to pH 3 with 3 N aqueoushydrochloric acid solution, and the precipitated crystals were collectedby filtration, and dried to give the title compound (5.00 g, yield; 90%)as brown crystals.

[0587] M.p. 108-110° C.

[0588] IR (KBr) 3420, 1737, 1627, 1568 cm⁻¹

[0589] Reference Example 6

[0590] Preparation of1-butyl-2-oxo-4-(3-bromo)phenyl-1,2-dihydropyridine-3-carboxylic acid:

[0591] The title compound was obtained in the same manner as inReference Example 5.

[0592]¹H NMR δ (CDCl₃) 1.01 (t, J=7.3 Hz, 3 H), 1.40-1.47 (m, 2 H), 1.79(m, 2 H), 4.11 (t, J=7.5 Hz, 2 H), 6.37 (d, J=7.0 Hz, 1 H), 7.20 (d,J=7.7 Hz, 1 H), 7.28 (dd, J=7.7, 7.7 Hz, 1 H), 7.40 (dd, J=2.0, 2.0 Hz,1 H), 7.53 (d, J=7.7 Hz, 1 H), 7.56 (d, J=7.0 Hz, 1 H)

[0593] M.p. 139-142° C.

[0594] IR (KBr) 3437, 1732, 1626, 1565 cm⁻¹

[0595] Reference Example 7

[0596] Preparation of1-butyl-2-oxo-4-(3-bromo)phenyl-5-methyl-1,2-dihydropyridine-3-carboxylicacid:

[0597] The title compound was obtained in the same manner as inReference Example 5.

[0598]¹H NMR δ (CDCl₃) 1.02 (t, J=7.3 Hz, 3 H), 1.41-1.48 (m, 2 H),1.79-1.86 (m, 2 H), 1.80 (s, 3 H), 4.09 (t, J=7.3 Hz, 2 H), 7.00 (ddd,J=1.5, 1.5, 7.7 Hz, 1 H), 7.20 (dd, J=1.5, 1.5 Hz, 1 H), 7.32 (dd,J=7.7, 7.7 Hz, 1 H), 7.44 (d, J=1.1 Hz, 1 H), 7.51 (ddd, J=1.1, 1.5, 7.7Hz, 1 H)

[0599] M.p. 197-198° C.

[0600] IR (KBr) 3437, 3068, 1732, 1633, 1564 cm⁻¹

[0601] Reference Example 8

[0602] Preparation of1-butyl-2-oxo-4-(5-bromo-2-methoxy)phenyl-1,2-dihydropyridine-3-carboxylicacid:

[0603] The title compound was obtained in the same manner as inReference Example 5.

[0604]¹H NMR δ (CDCl₃) 1.01 (t, J=7.3 Hz, 3 H), 1.38-1.57 (m, 2 H),1.79-1.89 (m, 2 H), 3.74 (s, 3 H), 4.03-4.16 (m, 2 H), 6.35 (d, J=6.8Hz, 1 H), 6.80 (d, J=8.8 Hz, 1 H), 7.19 (d, J=2.6 Hz, 1 H), 7.45 (dd,J=2.6, 8.8 Hz, 1 H), 7.56 (d, J=6.8 Hz, 1 H)

[0605] M.p. 179-180° C.

[0606] IR (KBr) 3436, 3033, 2969, 1720, 1623, 1568 cm⁻¹

[0607] Reference Example 9

[0608] Preparation of1-butyl-2-oxo-4-(2,5-dimethoxy)phenyl-1,2-dihydropyridine-3-carboxylicacid:

[0609] The title compound was obtained in the same manner as inReference Example 5.

[0610]¹H NMR δ (CDCl₃) 1.01 (t, J=7.5 Hz, 3 H), 1.45 (tq, J=7.5, 7.5 Hz,2 H), 1.84 (tt, J=7.5, 7.5 Hz, 2 H), 3.72 (s, 3 H), 3.77 (s, 3 H),4.01-4.12 (br, 2 H), 6.39 (d, J=6.8 Hz, 1 H), 6.67 (dd, J=0.7, 2.6 Hz, 1H), 6.84-6.88 (m, 2 H), 7.53 (d, J=6.8 Hz, 1 H)

[0611] Reference Example 10

[0612] Preparation of1-butyl-2-oxo-4-(2-methoxy-5-benzyloxy)phenyl-1,2-dihydropyridine-3-carboxylicacid:

[0613] The title compound was obtained in the same manner as inReference Example 5.

[0614]¹H NMR δ (CDCl₃) 1.01 (t, J=7.3 Hz, 3 H), 1.44 (tq, J=7.3, 7.3 Hz,2 H), 1.84 (tt, J=7.3, 7.3 Hz, 2 H), 3.72 (s, 3 H), 4.11 (br, 2 H), 5.01(s, 2 H), 6.37 (d, J=7.0 Hz, 1 H), 6.76 (d, J=3.1 Hz, 1 H), 6.85 (d,J=9.0 Hz, 1 H), 6.96 (dd, J=3.1, 9.0 Hz, 1 H), 7.30-7.44 (m, 5 H), 7.52(d, J=7.0 Hz, 1 H)

[0615] Reference Example 11

[0616] Preparation of1-butyl-2-oxo-4-(2-isopropoxy-4-benzyloxy)phenyl-1,2-dihydropyridine-3-carboxylicacid:

[0617] The title compound was obtained from1-acetyl-2-isopropoxy-4-benzyloxybenzene in the same manner as inReference Example 5.

[0618]¹H NMR δ (CDCl₃) 1.00 (t, J=7.3 Hz, 3 H), 1.23 (d, J=5.5 Hz, 6 H),1.43 (tq, J=7.3, 7.3 Hz, 2 H), 1.83 (tt, J=7.3, 7.3 Hz, 2H), 4.08 (br, 2H), 4.45 (qq, J=5.5, 5.5 Hz, 1 H), 5.06 (s, 2 H), 6.40 (d, J=6.8 Hz, 1H), 6.55 (d, J=2.2 Hz, 1 H), 6.59 (dd, J=2.2, 8.4 Hz, 1 H), 7.05 (d,J=8.4 Hz, 1 H), 7.31-7.49 (m, 6 H)

[0619] The ACAT inhibitory activity of the present compounds can beevaluated by the following method.

[0620] Experiment

[0621] 5 1. Assay of ACAT inhibitory activity in a specimen preparedfrom rabbit liver:

[0622] An enzyme specimen ACAT was prepared according to the methoddisclosed in the literature: J. Lipid. Research, 30, 681-690, 1989, fromthe liver of New Zealand white rabbit, which had been fed with 1%cholesterol feed for one month. The ACAT activity was determinedaccording to the method disclosed in the literature: J. Lipid Research,24, 1127-1134, 1983, i.e., using radioactive [1-¹⁴C]oleoyl-CoA andendogenous cholesterol contained in the liver microsome, and calculatedfrom the radioactivity of the labeled cholesterol oleate. The resultsare shown in Table 13. TABLE 13 Test compound ACAT inhibitory activity(Example No.) IC₅₀ (nM) 18 (hydrochloride) 295

[0623] 2. Assay of ACAT inhibitory activity in the macrophage derivedfrom rat peritoneal:

[0624] The rat peritoneal-derived macrophage was prepared according tothe method disclosed in the literature: Biochimica et Biophysica Acta,1126, 73-80, 1992. The ACAT activity was determined by a modified methodof the method disclosed in the above literature: Biochimica etBiophysica Acta, 1126, 73-80, 1992, i.e., using radioactive[9,10-³H]oleic acid and exogenous cholesterol contained in the liposomewhich was re-constituted according to the method disclosed in theliterature: Biochimica et Biophysica Acta, 1213, 127-134, 1994, andcalculated from the radioactivity of the labeled cholesterolyl oleate.The results are shown in Table 14. TABLE 14 Test compound ACATinhibitory activity (Example No.) IC₅₀ (nM) 18 (hydrochloride) 16

INDUSTRIAL APPLICABILITY

[0625] The pyridone derivative and the aminopyridone derivative cansafely be prepared by the present invention. Besides, the pyridonederivative of the present invention and a salt thereof strongly inhibitsACAT activity in a specimen of rabbit liver or in rat peritoneal-derivedmacrophage. Therefore, the pyridone derivative of the present inventionor a salt thereof is useful not only as an agent for treatment ofhyperlipidemia, but also in the prophylaxis or therapeutic treatment ofatherosclerosis per se or various diseases accompanied byatherosclerosis, for example, cerebral infarction, cerebral thrombosis,transient cerebral ischemia, angina pectoris, myocardial infarction,peripheral thrombus or occlusion.

1. A process for preparing a pyridone derivative of the formula (4):

wherein R is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, or a substituted cycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group; Y² and Y³ are independently a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a trifluoromethyl group, a nitro group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, a substituted aromatic group, or Y² and Y³ may combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring; and L is an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group, which comprises reacting a compound of the formula (1):

wherein R¹, Y¹, Y² and Y³ are as defined above, with a hypochlorite or a hypobromite or with lead tetraacetate to give a compound of the formula (2):

wherein R¹, Y¹, Y² and Y³ are as defined above, followed by reacting the compound (2) with a compound of the formula (3): L—NH₂  (3) wherein L is as defined above.
 2. The process according to claim 1 , wherein a sodium hypochlorite or a sodium hypobromite is used in the reaction from the compound (1) to the compound (2).
 3. The process according to claim 1 , wherein lead tetraacetate is used in the reaction from the compound (1) to the compound (2).
 4. The process for preparing the pyridone derivative according to any one of claims 1 to 3 , wherein Y² and Y³ combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a), (b) or (c):


5. The process for preparing the pyridone derivative according to any one of claims 1 to 3 , wherein Y² and Y³ combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a):


6. The process for preparing the pyridone derivative according to claim 4 or 5 , wherein Y¹ and L are a substituted aromatic group, and R¹ is a substituted or unsubstituted alkyl group.
 7. The process for preparing the pyridone derivative according to claim 6 , wherein Y¹ is a 3-methoxyphenyl group, L is a 2,6-diisopropylphenyl group, and R¹ is a butyl group.
 8. A process for preparing a pyridone derivative of the formula (4):

wherein R¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, or a substituted cycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group; Y² and Y³ are independently a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a trifluoromethyl group, a nitro group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, a substituted aromatic group, or Y² and Y³ may combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring; and L is an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group, which comprises reacting a compound of the formula (5):

wherein R¹, Y¹, Y² and Y³ are as defined above, with a compound of the formula (6): XCO₂R²  (6) wherein R² is a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted phenyl group; and X is a chorine atom or a bromine atom, to give a compound of the formula (7):

wherein R¹, R², Y¹, Y² and Y³ are as defined above, followed by reacting the compound (7) with a compound of the formula (3): L—NH₂  (3) wherein L is as defined above.
 9. The process for preparing the pyridone derivative according to claim 8 , wherein Y² and Y³ combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a), (b) or (c):


10. The process for preparing the pyridone derivative according to claim 8 , wherein Y² and Y³ combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a):


11. The process for preparing the pyridone derivative according to claim 9 or 10 , wherein Y¹ and L are a substituted aromatic group, and R¹ is a substituted or unsubstituted alkyl group.
 12. The process for preparing the pyridone derivative according to claim 11 , wherein Y¹ is a 3-methoxyphenyl group, L is a 2,6-diisopropylphenyl group, and R¹ is a butyl group.
 13. A process for preparing an aminopyridone derivative of the formula (5):

wherein R¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, or a substituted cycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group; and Y² and Y³ are independently a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a trifluoromethyl group, a nitro group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, a substituted aromatic group, or Y² and Y³ may combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, which comprises reacting a compound of the formula (1):

wherein R¹, Y¹, Y² and Y³ are as defined above, with a hypochlorite or a hypobromite or with lead tetraacetate to give a compound of the formula (2):

wherein R¹, Y¹, Y² and Y³ are as defined above, followed by subjecting the compound (2) to hydrolysis.
 14. The process for preparing the aminopyridone derivative according to claim 13 , wherein Y² and Y³ combine each other with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring together, and said pyridine ring is a group of the following formula (a), (b) or (c):


15. The process for preparing the aminopyridone derivative according to claim 13 , wherein Y² and Y³ combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a):


16. The process for preparing the aminopyridone derivative according to claim 14 or 15 , wherein Y¹ is a substituted aromatic group, and R¹ is a substituted or unsubstituted alkyl group.
 17. The process for preparing the aminopyridone derivative according to claim 16 , wherein Y¹ is a 3-methoxyphenyl group, and R¹ is a butyl group.
 18. A process for preparing an aminopyridone derivative of the formula (5):

wherein R¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, or a substituted cycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group; and Y² and Y³ are independently a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a trifluoromethyl group, a nitro group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, a substituted aromatic group, or Y² and Y³ may combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, which comprises heating a compound of the formula (8):

wherein R¹, Y¹, Y² and Y³ are as defined above, and Ring B is a substituted or unsubstituted benzene ring, in the presence of a base, to give a compound of the formula (9):

wherein R¹, Y¹, Y², Y³ and Ring B are as defined above, followed by removing the protecting phthaloyl group thereof.
 19. The process for preparing the aminopyridone derivative according to claim 18 , wherein Y² and Y³ combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a), (b) or (c):


20. The process for preparing the aminopyridone derivative according to claim 18 , wherein Y² and Y³ combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a):


21. The process for preparing the aminopyridone derivative according to claim 19 or 20 , wherein Y¹ is a substituted aromatic group, and R¹ is a substituted or unsubstituted alkyl group.
 22. The process for preparing the aminopyridone derivative according to claim 21 , wherein Y¹ is a 3-methoxyphenyl group, and R¹ is a butyl group.
 23. A process for preparing an aminopyridone derivative of the formula (5):

wherein R¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, or a substituted cycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group; and Y² and Y³ are independently a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a trifluoromethyl group, a nitro group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, a substituted aromatic group, or Y² and Y³ may combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, which comprises reacting a compound of the formula (1):

wherein R¹, Y¹, Y² and Y³ are as defined above, with a hypochlorite or a hypobromite.
 24. The process for preparing the aminopyridone derivative according to claim 23 , wherein Y² and Y³ combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a), (b) or (c):


25. The process for preparing the aminopyridone derivative according to claim 23 , wherein Y² and Y³ combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a):


26. The process for preparing the aminopyridone derivative according to claim 24 or 25 , wherein Y¹ is a substituted aromatic group, and R¹ is a substituted or unsubstituted alkyl group.
 27. The process for preparing the aminopyridone derivative according to claim 26 , wherein Y¹ is a 3-methoxyphenyl group, and R¹ is a butyl group.
 28. A process for preparing a pyridone derivative of the formula (4):

wherein R¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, or a substituted cycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group; Y² and Y³ are independently a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a trifluoromethyl group, a nitro group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, a substituted aromatic group, or Y² and Y³ may combine each other ring together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine; and L is an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group, which comprises reacting a compound of the formula (3): L—NH₂  (3) wherein L is as defined above, with a compound of the formula (6): XCO₂R²  (6) wherein R² is a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted phenyl group; and X is a chlorine atom or a bromine atom, to give a compound of the formula (32): L—NHCO₂R²  (32) wherein R² and L are as defined above, following by reacting the compound (32) with a compound of the formula (5):

wherein R¹, Y¹, Y² and Y³ are as defined above.
 29. The process for preparing the pyridone derivative according to claim 28 , wherein Y² and Y³ combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a), (b) or (c):


30. The process for preparing the pyridone derivative according to claim 28 , wherein Y² and Y³ combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a):


31. The process for preparing the pyridone derivative according to claim 29 or 30 , wherein Y¹ and L are a substituted aromatic group, and R¹ is a substituted or unsubstituted alkyl group.
 32. The process for preparing the pyridone derivative according to claim 31 , wherein Y¹ is a 3-methoxyphenyl group, L is a 2,6-diisopropylphenyl group, and R¹ is a butyl group.
 33. A process for preparing a pyridone derivative of the formula (4):

wherein R¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, or a substituted cycloalkyl group; Y¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group; Y² and Y³ are independently a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a trifluoromethyl group, a nitro group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, a substituted aromatic group, or Y² and Y³ may combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring; and L is an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group, which comprises reacting a compound of the formula (5):

wherein R¹, Y₁, Y² and Y³ are as defined above, with a compound of the formula (6): L—NCO  (31) wherein L is as defined above.
 34. The process for preparing the pyridone derivative according to claim 33 , wherein Y² and Y³ combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a), (b) or (c):


35. The process for preparing the pyridone derivative according to claim 33 , wherein Y² and Y³ combine each other together with the carbon atoms to which they bond, and form a substituted or unsubstituted pyridine ring, and said pyridine ring is a group of the following formula (a):


36. The process for preparing the pyridone derivative according to claim 34 or 35 , wherein Y¹ and L are a substituted aromatic group, and R¹ is a substituted or unsubstituted alkyl group.
 37. The process for preparing the pyridone derivative according to claim 36 , wherein Y¹ is a 3-methoxyphenyl group, L is a 2,6-diisopropylphenyl group, and R¹ is a butyl group.
 38. A pyridone derivative of the formula (10):

wherein L is an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group; Z is a direct bond or —NH—; R¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, or a substituted cycloalkyl group, provided that when Z is a direct bond, then R¹ is not a hydrogen atom; Y¹ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group; Y²² and Y³² are independently a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a trifluoromethyl group, a nitro group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group, or a salt thereof.
 39. The pyridone derivative according to claim 38 , or a salt thereof, wherein Z is —NH—.
 40. The pyridone derivative according to claim 39 , or a salt thereof, wherein Y¹ is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group.
 41. The pyridone derivative according to claim 39 or 40 , or a salt thereof, wherein one of Y¹, Y² and Y³ is an aromatic group or a substituted aromatic group.
 42. The pyridone derivative according to claim 39 , 40 , or 41, or a salt thereof, wherein L is an aromatic group or a substituted aromatic group.
 43. The pyridone derivative according to claim 42 , or a salt thereof, wherein one of Y¹, Y² and Y³ is a substituted phenyl group, and one of the substituents thereof is a group of the formula: —M¹—E—Q (M¹ is a direct bond, an oxygen atom, a sulfur atom or a group of the formula: —NR³— (R³ is a hydrogen atom or a lower alkyl group), E is a divalent aliphatic hydrocarbon group having 1 to 15 carbon atoms and optionally containing an unsaturated bond, or a phenylene group, Q is a hydrogen atom, a hydroxy group, a carboxyl group, a lower alkoxycarbonyl group, a benzyloxycarbonyl group, a halogen atom, a cyano group, a benzyloxy group, a lower alkoxy group, a lower alkanoyloxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a benzenesulfonyloxy group being optionally substituted by an alkyl group, a lower alkanoylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonamido group, a phthalimido group, a cycloalkyl group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a group of the formula: —NR⁴R⁵(R⁴ and R⁵ are independently a hydrogen atom, a lower alkyl group, a di-lower alkylamino-substituted lower alkyl group, a lower alkoxy-substituted lower alkyl group, a cycloalkyl group, a lower alkoxycarbonyl group, a heteroarylmethyl group, or an aralkyl group, or R⁴ and R⁵ may combine each other together with the nitrogen atom to which they bond, and form a saturated cyclic amino group having 4 to 8 carbon atoms as ones forming the said ring, and optionally having one —NR²⁰— (R²⁰ is a hydrogen atom, a lower alkyl group, a phenyl group, a lower alkoxycarbonyl group, or a benzyl group) or one oxygen atom in the cycle thereof), or a group of the formula: —C(═O)NR⁴R⁵ (R⁴ and R⁵ are as defined above)).
 44. The pyridone derivative according to claim 43 , or a salt thereof, wherein Y¹ is a substituted phenyl group.
 45. The pyridone derivative according to claim 44 , or a salt thereof, wherein M¹ is an oxygen atom.
 46. The pyridone derivative according to claim 43 , 44 , or 45, or a salt thereof, wherein Q is a hydrogen atom, a hydroxy group, a carboxyl group, a lower alkoxycarbonyl group, a benzyloxycarbonyl group, a benzyloxy group, a lower alkoxy group, a lower alkanoyloxy group, a lower alkanoylamino group, a heteroaryl group, a substituted heteroaryl group, or a group of the formula: —NR⁴R⁵.
 47. The pyridone derivative according to claim 46 , or a salt thereof, wherein E is an alkylene group having 1 to 4 carbon atoms, and Q is a substituted or unsubstituted pyridyl group, a 1,2,4-triazol-1-yl group, or a group of the formula: —NR⁴R⁵.
 48. The pyridone derivative according to claim 43 or 44 , or a salt thereof, wherein M¹ is a direct bond.
 49. The pyridone derivative according to claim 48 , or a salt thereof, wherein Q is a hydrogen atom, a hydroxy group, a carboxyl group, a lower alkoxycarbonyl group, a benzyloxycarbonyl group, a benzyloxy group, a lower alkoxy group, a lower alkanoyloxy group, a lower alkanoylamino group, a heteroaryl group, a substituted heteroaryl group, or a group of the formula: —NR⁴R⁵.
 50. The pyridone derivative according to claim 48 or 49 , or a salt thereof, wherein —E— is a group of the formula:

(wherein R⁶ and R⁷ are independently a hydrogen atom, a methyl group, an ethyl group, or a propyl group, or R⁶ and R⁷ may combine each other to form a 3- to 7-membered cycloalkane ring, m is an integer of 0 to 6, and p is an integer of 0 to 6).
 51. The pyridone derivative according to claim 50 , or a salt thereof, wherein p is
 0. 52. The pyridone derivative according to claim 51 , or a salt thereof, wherein R⁶ and R⁷ are both hydrogen atoms, and m is 0 or
 1. 53. The pyridone derivative according to claim 47 or 52 , or a salt thereof, wherein R¹ is an alkyl group, a substituted alkyl group, or a hydrogen atom.
 54. The pyridone derivative according to claim 53 , or a salt thereof, wherein Y²² and Y³² are hydrogen atoms.
 55. A pharmaceutical composition containing a pyridone derivative as set forth in any one of claims 38 to 54 , or a salt thereof.
 56. An acyl-CoA: cholesterol acyl transferase (ACAT) inhibitor, which contains as an active ingredient a pyridone derivative as set forth in any one of claims 38 to 54 , or a salt thereof.
 57. An agent for treatment of hyperlipidemia or atherosclerosis, which contains as an active ingredient a pyridone derivative as set forth in any one of claims 38 to 54 , or a salt thereof.
 58. A method for inhibiting acyl-CoA: cholesterol acyl transferase (ACAT), which comprises administering an effective amount salt thereof, to a patient in need thereof.
 59. A method for treatment of hyperlipidemia or atherosclerosis, which comprises administering an effective amount of a pyridone derivative as set forth in any one of claims 38 to 54 , or a salt thereof, to a patient in need thereof.
 60. Use of a pyridone derivative as set forth in any one of claims 38 to 54 , or a salt thereof, in preparation of a pharmaceutical composition for inhibiting acyl-CoA: cholesterol acyl transferase (ACAT).
 61. Use of a pyridone derivative as set forth in any one of claims 38 to 54 , or a salt thereof, in preparation of an agent for treatment of hyperlipidemia or atherosclerosis. 